IE66711B1 - 2-(heterocyclylthio) carbapenem derivatives their preparation and their use as antibiotics - Google Patents

Abstract

Compounds of formula (I): <CHEM> in which R<a> is a group of formula (II): <CHEM> or a group of formula (III): <CHEM> (where one of R min is a bond to the remainder of the compound, one more of R min is R<2> and the others of R min are all hydrogen), R<1> is hydrogen or methyl, R<2> is hydrogen, optionally substituted alkyl, halogen, hydroxy, alkoxy, amino, alkanoylamino, alkanoyloxy, alkanoyl, carboxy, alkoxycarbonyl, cyano, -S(O)jR<9> (where j is 0, 1 or 2 and R<9> is alkyl), or -CONR<6>R<7> (which is optionally subsituted carbamoyl or heterocyclyl-carbonyl), R<2a> is hydrogen, alkyl or alkanoyl, -NR<3>R<4> is optionally substituted amino or heterocyclic, and -COOR<5> is carboxy, -COO<->, -COOMx (where M is a cation and x is the reciprocal of the valence of the cation M) or protected carboxy and, where -COOR<5> is carboxy, -COOMx or protected carboxy, the compound of formula (I) also contains an anion; l , m and n are independently 0, 1, 2 or 3, provided that (m + n) is an integer from 2 to 6; p is 0, 1 or 2; Y is a single bond, oxygen, sulphur or R<8>N< (wherein R<8> is hydrogen, alkyl or alkanoyl) and pharmaceutically acceptable salts and esters thereof are potentially valuable antibiotics.

Description

The present invention relates to a series of new carbapenem compounds. co methods using these compounds and to compositions containing these compounds, and provides processes for preparing these compounds.

The penicillins form a well known class of antibiotics, which have found considerable use in human and animal therapy for many years. Chemically, the penicillins have in common a β-lactam structure, commonly referred to as penam, which may be represented by the following formula: S I \ b <*> I (A) However, although the penicillins still form a valuable weapon in the pharmaceutical armory, the development of new, and often penicillin-resistant, strains of pathogenic bacteria has increasingly made it necessary to search for new types of antibiotic. < .

In recent years, great interest has been shown in -«s compounds having a carbapenem structure, that is ; compounds having a carbon atom in place of the sulphur atom at the l-position and having a double bond between the carbon atoms in the 2- and 3-positions of the basic penam structure. The carbapenem structure may be represented by the following formula: *~7 c O I | 1 i * / \ S.-.5 -2 I I II (3) 7*-M-»3.

I 1 These penam and carbapenem structures form the basis for the semi-systematic nomenclature of the penicillin derivatives in accordance with the recommendations of the International Union of Shire and Applied Chemistry (IUPAC)and this nomenclature is generally accepted by those skilled in the art throughout the world and is used herein. The numbering system employed herein is that Illustrated on the above formula (B).

Of the known carbapenem derivatives, the best known is a compound called Kthienamycin®, whose semi-systematic name is 2-(2-aminoethylthio)6-(1-hydroxyethyl)carbapen-2-em-3-carboxylic acid. Although thienamycin is known to have remarkably potent and broad antibacterial activity,, its chemical stability in the human body Is poor, which restricts its practical use. Various attempts have, therefore, been made to modify the chemical structure of thienamycin in order to improve its chemical stability whilst maintaining or improving its superior activity, but there is still a continuing need to develop further carbapenem antibiotics with improved properties.

The present invention provides a new group of carbapenem derivatives which possess superior absorption and metabolic stability (as evidenced by improved recovery rates in the urine), as well as a broad antibacterial spectrum and low toxicity. The invention also provides synthetic processes for the preparation of the new carbapenem derivatives, as well as pharmaceutical compositions comprising the said derivatives suitable for human and animal administration.

Of the prior art known to us, the following are believed to be the closest: US Patent Specifications No. 4 640 799 and No. 665 170 disclose carbapenem compounds in which there is a group -S-A-N+ at the 2-position. Aa can be various groups, and N* represents a ouatemized nitrogen-containing heterocyclic group attached to A through its quaternary nitrogen atom. These compounds differ from those of the present invention in that, where the compounds of the present invention contain a quatemized nitrogen-containing heterocyclic group having a quaternary nitrogen atom, this is not attached to the rest of the molecule via the quaternary nitrogen atom, but is attached via a carbon atom of the heterocyclic group.

European Patent Specification No. 126 587 discloses a series of carbapenem compounds having a pyrrolidinylthio group at the 2-position. These differ from the compounds of the present invention which are quaternary nitrogen compounds in that these prior art compounds are not quaternary nitrogen compounds and they differ from the non-quat©raized compounds of the present invention in the nature of the substituents on the heterocyclic ring. Certain of the compounds disclosed in this prior art may have good activity, but they are believed, to be less well absorbed in vivo than are the compounds of the present invention.

European Patent Publications Nos. 72,710 and 235,823 also disclose carbapenem compounds structurally similar to those of the present application. Certain compounds of EP 72,710 have a non-aromatic haterocyclyIthio group at the 2-position of the carbapenem structure. Certain compounds in EP 235,823 include a 2-position non-aromatic heterocycle containing a quatemised 5 nitrogen atom. Similarly to the compounds of US 4,665,170 and US 4,640,799, however, this ring is attached to the remainder of the compound via its quatemised nitrogen atom.

The compounds of the present invention may be represented by the formula (I) : HO H R1 \ / I C C-H / \ / \ H3C CH—CH C-S-(CH2)a-Ra (I) -W-c COOR5 in which: Ra represents a group of formula (III) Rf R \ / C R / \ / (CR’2)o c Γ l\ N-C Rf J R2a O (III) and in which: one of the symbols R represents a bond to the remainder 35 of the compound of formula (I) t in said group of formula (III) the others of the symbols Re all represent hydrogen atoms; R1 represents a methyl group; 2a R represents a hydrogen atom, a - Cg alkyl group or a C.. - Cg alkanoyl group; and -COOR represents a carboxy group, a group of formula -C00\ a group of formula -COOM^, where M is a cation and x is the reciprocal of the valence of the cation M, or a protected carboxy group and, where s -COOR represents a carboxy group, a group of formula -COOM or a protected carboxy group, the compound of formula (I) also contains an anion; X is zero, or an integer from 1 co 3; n is zero or the integer 1 or 2; and pharmaceutically acceptable salts and esters thereof.

For the following description, the definition of substituents (a) and substituents (c) is relevant: substituents (a): hydroxy groups, cyano groups, carbamoyloxy groups, azido groups, carboxy groups, nitro groups,, oxo groups, halogen atoms, - Cg alkoxy groups, Cn - Cg alkanoyl groups, C1 - Cg alkanoyloxy groups, C„ - alkanoylamino groups, Co - C. - © ' - * iq χι alkoxycarbonyl groups, groups of formula -NR~ R 12 1 3 •and -CONRi"R-'J in which R10, R11, R12 and R13 are the same or different and each represents a hydrogen atom, a - Cg alkyl group or a - Cg alkanoyl group, τ5 IS groups of formula -SO2&R R* and -S(O)kR z wherein R1^, R15 and R18 are the same or i different and each represents a C., - Cg alkyl group and Jt is zero or an. integer 1 or 2.. and groups of formula -^jHS0oR1z, -N-CR18NR1SR20, -N=CR21CR22=NR23 and -C(=NH)NR24R25 wherein R to R are the same or different and each represents a hydrogen atom or a C, « CL alkyl group; substituents (c): Cx - alkyl groups, alkoxy groups, Cx - C4 haloalkyl groups, ~C3 alkylenedioxy groups, halogen atoms, cyano groups and nitro groups.

The invention also provides a pharmaceutical composition comprising an effective amount of an antibiotic in admixture with a pharmaceutically acceptable carrier or diluent, wherein the antibiotic is at least one compound selected from the group consisting of compounds of formula (I) and pharmaceutically acceptable salts and esters thereof.

The invention still further provides the use for the -I 7 manufacture of a medicament for the treatment or prevention of microbial infection (e.g. in a mammal, which may be human) of an antibiotic, wherein the antibiotic is at least one compound of formula. (I) or a pharmaceutically acceptable salt or ester thereof.

The invention also provides processes for preparing the compounds of the present invention, which are described in more detail hereinafter.

In the compounds of the present invention, where 2a R represents an alkyl group, this may be a straight or branched chain alkyl group containing from l to 6 carbon atoms, and examples include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, hexyl, isohexyl and 2-methylpentyl groups, of which the methyl, ethyl, propyl and butyl groups are preferred, the methyl group generally being most preferred.

Where R~ or substituent (a) represents an alkanoyl group, this may be a straight or branched chain alkanoyl group containing from 1 to 6 carbon atoms, and examples include the formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and hexanoyl groups, of which the formyl and acetyl groups are more preferred.

Where substituent (a) represents an alkanoylamino group, this may be a straight or branched chain alkanoylamino group containing from 1 to 6 carbon atoms, and examples include the formamido, acetamido, propionamido, butyramido, isobutyramido, valerylamino, isovalerylamino, pivaloylamino and hexanoylamino groups, of which the acetamido group is more preferred.

Where substituent (a) represents an alkanoyloxy group, this may be a straight or branched chain alkanoyloxy group containing from I to 6 carbon atoms, and examples include the formyloxy, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy and hexanoyloxy groups, of which the acetoxy, propionyloxy, butyryloxy, isobutyryloxy and pivaloyloxy groups are more preferred, and the acetoxy group is most preferred.

' Where substituent (a) represents a halogen atom, this may be a fluorine, chlorine, iodine or bromine v atom, of which the fluorine, chlorine and bromine atoms are preferred, the fluorine and chlorine atoms being most preferred.

Were substituent (a) represents an alkoxy group, this may be a straight or branched chain alkoxy group containing from 1 to 6 cartoon atoms, and examples include the methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy, isopentyloxy, 2-methyIbutoxy, hexyloxy, isohexyloxy and 2-methylpentyloxy groups, of which the methoxy, ethoxy, propoxy and butoxy groups are preferred, the methoxy group generally being most preferred.

Where substituent (a) represents an alkoxycarbonyl group, this may be a straight or branched chain alkoxy group containing, in total, from 2 to 7 carbon atoms, including the carbon atom of the carbonyl group (i.e, the alkoxy part contains from 1 to S carbon atoms), and examples include the methoxycarbonyl, ethoxycarbonyl , propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, t - butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarboayl, 2-methvlbutoxycarbonyl, hexyloxycarbonyl, ί isohexyloxycarbonyl and 2-methylpentyloxycarbonyl . groups, of which the methoxycarbonyl and ethoxycarbonyl groups are most preferred.

Specific examples of atoms and groups which are included, within substituents (a) include: hydroxy groups, cyano groups, carbamoyloxy groups. azido groups, carboxy groups, nitro groups and oxo groups; halogen atoms, such as the chlorine, fluorine, bromine and iodine atoms, especially the chlorine and fluorine atoms; Ci CS alkoxy groups, - Cg alkanoyl groups, - Cg alkanoyloxy groups, - Cg alkanoylamino groups and - C_ alkoirutarbonyl groups, as exemplified above; groups of formula -NR1OR1X and -CONRX2R13, i.e. amino and carbamoyl groups and alkyl-substituted and alkanoyl-substituted derivatives thereof, such as the amino, methylamino, ethylarnino, propylamino, isopropylaad.no, butylamino, isobutylamino, sec-butylamino, t-buty lamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, carbamoyl, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, sec-butylcarbamoyl, t-butylcarbamoyl, dime thylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl, diisopropylcarbamoyl, dibutyl carbamoyl, formamido, acetamido, propionamido, butyramido, isobutyramido, valerylamino, isovalerylamino, pivaloylamino, hexanoylamino formyl carbamoyl, acetylcarbamoyl, propionylcarbamoyl, butyrylcarbamoyl, isobutyryl carbamoyl, valerylamino, isovalerylamino, pivaloylcarbamoyl and hexanoylcarbamoyl groups; ι ς groups of formula SO-NR R and g -SiOJ^R , i.e. sulphamoyl, thio, sulphinyl and sulphonyl groups, for example the methylsulphamoyl, ethylsulphamoyl, propylsulphamoyl, isopropylsulphamoyl, butylsulphamoyl, isobutylsulphamoyl, sec-butylsulphamoyl, t-butylsulphamoyl, dimethylsulphamoyl, diethylsulphamoyl, dipropylsulphamoyl„ diisopropylsulphamoyl, dibutylsulphamoyl, and the thio, sulphinyl and sulphonyl groups exemplified for 2 2 R where R" represents a group of formula ~S(O)_.R9; groups of formula. -NHSO_R17, -N=CR18NR19R20, ~N=CR21CR22«NR23 and -C(=NH)NR24R25, in which Rlz to R25 are as defined and exemplified above.

R5 represents a hydrogen atom or a protecting group, which is capable of removal under chemically moderate conditions such as by means of a chemical reducing reagent or by catalytic reduction, or which is capable of removal by means of biological reactions, e.g. in vivo, to produce a carboxy group. There is no limitation upon the nature of such a protecting group, provided that, where the resulting compound is to be used for therapeutic purposes, it is pharmaceutically acceptable, which, as is well-known in the art, means that the compound does not have reduced activity (or unacceptably reduced activity) or increased toxicity (or unacceptably increased toxicity) compared with the 5 corresponding compound of formula (I) where R represents a hydrogen atom. Where, however, the compound is to be used for non-therapeutic purposes, e.g. as an intermediate in the preparation of other compounds, even this limitation does not apply, and the •protecting group may be chosen having regard simply to process criteria. Examples of groups which may be represented by R include: cl " C20 al^cy1 groups, more preferably C1 ‘ C6 groups, such as those exemplified in relation to R2 etc. and higher alkyl groups as < are well known in the art, such as the heptyl, octyl, nonyl and decyl groups, but most preferably % the methyl, ethyl and t-butyl groups; - C„ cycloalkyl groups, for example where the cycloalkyl group is any one of those - Cg cycloalkyl groups described herein in relation to S 7 R and R or the cycloheptyl group; aralkyl groups, as defined and exemplified above in *" 3 4 relation to R and R but in which the aromatic group is Cg - C14, which may be substituted or unsubstituted, and, if substituted may have at least one of substituents (c), defined above and exemplified below; examples of such aralkyl groups include the benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, l-naphthylmethyl, -naphthylmethyl, 2-(1-naphthyl) ethyl, 2-(2-naphthyl) ethyl, benzhydryl (i.e. diphenylmethyl), triphenylmethyl, bis(q-nitrophenyl)methyl, 9-anthrylmethyl, 2,4,6-trimethyl25 benzyl, 4-bromobenzyl, 2-nitrobenzyl, 4-nitrobenzyl, 2-nitrobenzyl, 4-methoxybenzyl and piperonyl groups; alkenyl groups such as those defined and exemplified A above in relation to R and R", but which may be substituted or unsubstituted and, if substituted have at least one of substituents (a) defined above; v examples of the unsubstituted groups are given above £. in relation to R and R, and preferred groups Include the allyl, 2-chloroallyl and 2-methylallyl groups,halogenated - Cg, preferably C.,( - CA, alkyl groups ia which the alkyl part is as defined and exemplified in relation to the alkyl groups 2 which may be represented by R etc, and the halogen atom is chlorine, fluorine, bromine or iodine, such as the 2,2,2"trichloroethyl, 2-haloethyl (e.g. 2-chloroethyl, 2-fluoroethyl, 2-bromoethyl or 2-iodoethyl), 2,2-dibromoethyl and 2,2,2-tribromoethyl group ; substituted silylalkyl groups, in which the alkyl part is as defined and exemplified in relation to 2 the alkyl groups which may be represented by R etc, and the silyl group has up to 3 substituents selected from the group consisting of - Cg alkyl groups and phenyl groups which are unsubstituted or have at least one of substituents (a) defined and exemplified above, for example a 2 -1rimethylsilylethyl group; phenyl groups, in which the phenyl group is unsubstituted or substituted, preferably with at least one C1-C^ alkyl or acylamino group, for example the phenyl, tolyl and benzamidophenyl groups; phenacyl groups, which may be unsubstituted or have at least one of substituents (a) defined and exemplified above, for example the phenacyl group itself or the p-bromophenacyl group; cyclic and acyclic terpenyl groups, for example the geranyl, neryl, linalyl, phytyl, menthyl (especially S3- and p~ menthyl), thujyl, caryl, pinanyl, bornyl, notcaryl, norpinanyl, norbomyl, menthenyl, camphenyl and norbomenyl groups; alkoxymethyl groups, in which the alkoxy part is CT - Cg, preferably - C^, and may itself be substituted by a single unsubstituted alkoxy group, such as the methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl and methoxyethoxymethyl groups ; aliphatic acyloxymethyl groups, in which the acyl group is preferably an alkanoyl group and is more preferably a C2 - Cg alkanoyl group, such as the acetoxymethyl, propionyloxymethyl, butyryloxymethy1, isobutyryloxymethyl and pivaloyloxymethyl groups; higher aliphatic acyloxyalkyl groups in which the acyl group is preferably an alkanoyl group and is more preferably a - Cg alkanoyl group, and the alkyl part is - Cg, and preferably C2 ’ C4' suchL as 1-pivaioyi-oxyettiyif» 1- acetoxyethyl, 1-isobutyryloxyethyl, 1-pivaloyloxypropyl, 2-methyl-X-pivaloyl oxypropyl, 2-pivaloyloxypropy1, 1-isobutyryloxyethyl, 1-isobutyryloxy 20 propyl, X-acetoxypropyl, l-acetoxy~2-methylpropyl, - propionyl oxyethyl, X - propionyl oxypropyl, 2- acetoxypropyl and X-hutyryloxyethyl groups; cycloalkvl-substituted aliphatic acyloxyalkyl groups, in which the acyl group is preferably an alkanoyl group and is more preferably a - C, alkanoyl group, the cycloalkyl substituent is C3 - Gj, and the alkyl part is a Cn - Cg alkyl group, preferably a C1 - alkyl group, such as the (cyclohexylacetoxy)methyl, X-(cyclohexylacetoxy) ethyl, X - (cyclohexylacetoxy) propyl, 2-methyl-X- (cyclohexylacetoxy)propyl, . (cyclopentylacetoxy)methyl, X- (cyclopentylacetoxy) ethyl, X -.(cyclopentylacetoxy) propyl and 2 -methyl - X 35 (cyclopentylacetoxy) propyl, groups; alkoxycarbonyloxyalkyl groups, especially 1- (alkoxycarbonyloxy)ethyl groups, in which the alkoxy part is C., - C1QP preferably - Cg, and more preferably C„ - CA, and the alkyl part is C^ - Cg, preferably Cn - C^, such as the -me thoxy carbonyl oxyethyl, 1 - ethoxycarbonyloxyethyl, -propoxycarbonyloxyethyl, 1~ isopropoxycarbonyl oxyethyl, 1-butoxycarbonyloxyethyl, 1-isobutoxycarbonyloxyethyl, 1-sec-butoxycarbonyloxyethyl, -1 -butoxycarbonyloxyethyl, 1-(1-ethylpropoxycarbonyloxy)ethyl and 1- (1,1-dipropylbutoxycarbonyloxy) ethyl groups, and other alkoxycarbonylalkyl groups, in which both the alkoxy and alkyl groups are - Cg, preferably C1 - C^, such as the -methyl -1 - (isopropoxycarbonyloxy) propyl, 2- (isopropoxycarbonyloxy)propyl, isopropoxycarbonyloxymethyl, t-butoxycarbonyloxymethyle methoxy~ carbonyloxymethyl and ethoxycarbonyloxymethyl groups; cycloalkylcarbonyloxyalkyl and cycloalkyloxycarbonyloxyalkyl groups, in which the cycloalkyl group is C3 · C-,θ, preferably C3 - C„, is mono- or poly- cyclic and is optionally substituted by at least one (and preferably only one) alkyl group (e.g. selected from those alkyl groups exemplified above) and the alkvl group is a C1 - Cg, more preferably - CA, alkyl group (e.g. selected from those alkyl groups exemplified above) and is most preferably methyl, ethyl or propyl, for example the 1-methylcyclohexylcarbonyloxymethyl, i-methylcyclohexyloxycarbonyloxymethyl , cycl open tyl oxy carbonyl oxymethyl, cyclo pentylcarbonyloxymethyl, l - cyclohexyloxycarbonyl oxyethyl, l-eyclohexylcarbonyloxyethyl, 1-cyclopentyl oxy carbonyl oxy ethyl , 1-cyclopentylcarbonyloxyethyl, 1-cycioheptyloxycarbonyloxyethyl, 1-cycloheptyl carbonyl oxyethyl, 1 -methyl cyclopentyl carbonyl oxymethyl, X - methyl cyclopentyloxycarbonyloxymethyl, -methyl -1-(1 -methyl cyclohexylcarhonyloxy) propyl, 1- (1 -methylcyclohexylcarbonyloxy) propyl, - (X -me thyl cyclohexyl carbonyloxy) propyl, 1- (cyclohexylcarbonyloxy)propyl„ 2-(cyclohexylcarbonyl oxy) propyl, 2 -methyl -1-(1 -methyl cyclopentyl carbonyloxy) propyl, 1-(1 -methyl cyclopentyl carbonyl oxy)propyl, 2-(1-methylcyclopentylcarbonyloxy)propyl, 1-(cyclopentylcarbonyloxy)propyl, 2-(cyclopentylcarbonyloxy) propyl, 1- (1- me thyleye1openty1carbonyloxy) ethyl , 1( 1 -met hyl cyclopentyl carbonyl oxy)propyl„ adamantyloxycarbonyloxymethyl, adamantvlcarbonyloxymethyl e 1 -adamantyloxycarbonyl oxyethyl and 1-adamantylcarbonyloxyethyl groups; cycloalkylalkoxycarbonyloxyalkyl groups in which the alkoxy group has a single cycloalkyl substituent, the cycloalkyl substituent being - C1Q, preferably - ¢--. and mono- or poly- cyclic, for example the cyclopropylmethoxycarbonyloxymethyl, cyclobutylmethoxycarbonyloxymethyl, cyclopentylmethoxycarbonyloxymethyl, cyclohexylmethoxycarbonyl oxymethy1, 1-(cyclopropylmethoxycarbonyloxy) ethyl, 1- (cyclobutylme thoxycarbonyloxy) ethyl, 1-(cyclopentylmethoxycarbonyloxy)ethyl and 1-(cyclohexylmethoxycarbonyloxy)ethyl groups; terpenylcarbonyloxyalkyl and terpenyloxycarbonyl oxyalkyl groups, in which the terpenyl group is as exemplified above in relation to the terpenyl groups 5 which may be represented by R , and is preferably a cyclic terpenyl group, for example the X-(menthyloxycarbonyloxy) ethyl e 1 - (menthylcarbonyloxy) ethyl, menthyloxycarbonyloxymethyl, menthylcarbonyloxymethyl, 1-(3-pinanyloxycarbonyloxy) ethyl, 1-(3-pinanyicarbonyloxy) ethyl, 3-pinanyloxycarbonyl oxymethyl and 3-pinanylcarbonyloxymethyl groups; IS -alkyl or 5-phenyl (which may he substituted by at least one of substituents (c)] (2-oxo-1,3-dioxolen4-yl)alkyl groups in which each alkyl group (which may be the same or different) is CL - C...

X o preferably - C„, for example the (5-methyl- 2 -oxo-1,3-dioxolen-4-yl)methyl, (5-phenyl-2-oxo-1,3-dioxolen-4-y1) methyl, (5-isopropyl- 2 -oxo-1,3-dioxolen-4-yl)methyl, (5-1-butyl-2 -oxo-1,3-dioxolen-4-yl)methyl and l-(5~met&yl-2-oxo-l,3-diQxolen-4-yl)ethyl groups; and other groups, especially groups which are easily removed in vivo such as the phthalidyl, indanyl and 2-oxo-4,5,6,7-tetrahydro-1,3-benzodioxolen-4-yl groups.

Of the above groups, we especially prefer those groups which can be removed easily in vivo, and most preferably the aliphatic acyloxymethyl groups, higher aliphatic acyloxyalkyl groups, cycloalkyl-aliphatic acyloxyalkyl groups, alkoxycarbonyloxyalkyl groups, cycloalkylcarbonyloxyalkyl groups, and cycloalkylalkoxycarbonyloxyalkyl groups.

The compounds of the present invention can contain a basic group and can, therefore, form acid addition salts. The nature of such salts and such acids is not critical to the invention, provided that, where the compound is intended for use therapeutically, the salt is pharmaceutically acceptable, which, as is well known, means that it does not have a lower (or significantly lower) activity or a higher (or significantly higher) toxicity than the free base. However, where the compound is Intended for other uses, e.g. as an intermediate in the preparation of other compounds, even this limitation does not apply.

Examples of acids which can form such salts or can provide the balancing anion include: inorganic acids, such as hydrochloric e.cid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulphuric acid or nitric acid; organic sulphonic acids, such as methanesulphonic acid, ethanesulphonic acid, foenzenesulphonic acid or n-toluenesulphonic acid; and organic carboxylic acids, such as oxalic acid, tartaric acid, citric acid, maleic acid, succinic acid, acetic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid and malic acid.

Examples of cations which may foe represented M in the compounds of the present invention include: metal atoms, especially alkali metal atoms, such as the sodium and potassium atoms, and alkaline earth metal atoms, such as the calcium atom; the ammonium group; and cations derived from a trialkylamine, such as triethylamine, or from another organic base, such as procaine, dibenzylamine or phenethylamine.

Where the compound of the invention is an ester, i.e. R5 represents a protecting group, we prefer those in which: g R represents: a C_ - C^q alkyl group, more preferably a - Cg alkyl group; a C3 - C7 cycloalkyl group; an aralkyl group in which the alkyl part is - C3 and the aromatic group is Cg - C.^ and is unsubstituted or has at least one of substituents (c), defined above; a C, - Cg alkenyl, group which Is unsubstituted or has at least one of substituents (a) defined above; a halogenated Cx ~ Cg, preferably C^ - CA, alkyl group; a substituted silylalkyl group in which each alkyl part is ci C6 an<^ fciie silyl group has up to 3 substituents selected from the group consisting of C... - Cg alkyl groups and phenyl groups which are unsubstituted or have at least one of substituents (a) defined above; a phenyl group which is unsubstituted or has at least one alkyl or acylamino substituent; a phenacyl group which is unsubstituted or has at least one of substituents (a) defined above; a cyclic or acyclic terpenyl group; an alkoxymethyl group, in which the alkoxy part is - Cg, preferably - C4, which is unsubstituted or is itself substituted by a single unsubstituted alkoxy group; an aliphatic acyloxymethyl group, in which the acyl group is preferably an alkanoyl group and is more preferably a C2 ' C6 alkan°yl group; a higher aliphatic acyloxyalkyl group in which the acyl group is preferably an alkanoyl group and is snore preferably a - Cg alkanoyl group, and the alkyl part is - Cg, and preferably C? - C4; a cycloalkvl-substituted aliphatic acyloxyalkyl group, in which the acyl group is preferably an alkanoyl group and Is more preferably a C2 - Cg alkanoyl group, the cycloalkvl substituent is C3 - C?, and the alkyl part is a Cx - Cg alkyl group, preferably a C. - alkyl group; an alkoxycarbonyloxyalkyl group, especially a 1-(alkoxycarbonyloxy)ethyl group, in which the alkoxy part is C, - C1Q, preferably C1 - Cg, and more preferably - CA, and the alkyl part is - Cg, preferably - C4; a cycloalkylcarbonyloxyalkyl or cycloalkyloxycarbonyloxyalkyl group, in which the cycloalkvl group is C3 - C1Q, preferably C3 ~ C7 Is mono- or poly- cyclic and is optionally substituted by at least one - C4 alkyl .group, and the alkyl group is a C1 - Cg„ more preferably C„ - C^, alkyl group; a cycloalkylalkoxycarbonyloxyalkyl group in which the alkoxy group has a single cycloalkyl substituent, the cycloalkyl' substituent being C3 - C10# preferably C3 - ,. and mono- or poly- cyclic; a terpenylcarbonyloxyaXkyl or terpenyloxycarbonyloxyalkyl group; a 5-alkyl- or 5-phenyl- substituted (2-oxo-i, 3-dioxolen-4-yl)alkyl group in which each alkyl group is CL - Cg, preferably - C^, and in which the phenyl group is unsubstituted or has at least one of substituents (c); a phthalxdyl group; an xndanyl group; or a 2-oxo-4,5,6,7-tetrahydro-l,3-benzodioxolen4-yl group. a Of the compounds of the present invention where R represents a group of formula (III), -5 prefer; (C) those in which: p is 1, and particularly where the group of formula (III) is a pyrrolxdin-2-one-4-yl group, which has the 2a group R at its nitrogen atom; and 2a R is a hydrogen atom, a alkyl group, more preferably a methyl, ethyl, propyl or butyl group, or a C4 alkanoyl group, more preferably a formyl, acetyl, propionyl or butyryl group, and is most preferably a hydrogen atom, i.e. the pyrrolidxn-2-one-4-yl group is unsubstituted.

The compounds of formula (I) can exist xn the form of various isomers because of the presence of asymmetric carbon atoms. Both the individual isomers and mixtures of two or more isomers are included in the present invention. Such mixtures may be prepared as a result of the synthesis reactions or by mixing. Where an individual isomer is required, this may be prepared by a stereo-specific synthesis route or it may be prepared by separating a mixture of isomers, using separation techniques well known in the art. We particularly prefer those compounds in which the 1-hydroxyethyl group at the 6-penem position is in the same configuration as thienamycin, i.e. it is 1 (R) -hydroxyethyl. Also, when R1 represents a hydrogen atom, the (5R, S£) configuration Is preferred, and, when R~ represents a methyl group, the (IR, 5S, SS) configuration is preferred.

Specific Examples of compounds of the invention are given in the following formulae (1-8) and (1-9), in which the substituents are as defined in the corresponding one of Tables 8 and 9 [i.e. Table 8 relates to formula (1-8), Table 9 relates to formula. (1-9)] .

In the Tables, the following abbreviations are used: Ί5 Ac acetyl Ada adamantyl All allyl Azr aziridinyl Azt azetidinyl Bu butyl cBu cyclobutyl gBu sec-butyl tBu t-butyl Byr butyryl iByr isobutyryl Bz benzyl Car carbamoyl Dix 2-oxo-l,3-dioxolen-4-yl Dox (5-methyl-2-oxo-Ι,3-dioxolen 4-yl)methyl Et ethyl Etc ethoxycarbonyl £Hp cycloheptyl CHx cyclohexyl He methyl Mec methoxycarbonyl Men . menthyl Mor morpholino Pdox (5-phenyl- 2 -oxo-1,3-dioxo' 4-yl)methyl Ph phenyl Phth phthalidyl Pip piperidyl Piv pivaloyl Piz piperazinyl £PX1 cyclopentyl Pr propyl cPr cyclopropyl iPr isopropyl Prg propargyl ( = 2-propynyl) Pm propionyl Pvrd pyrrolidinyl Tfm trifluoromethyl Thz perhydro-1,4-thiazin-4-yl (= thiomorpholino) ΗΟχ/Ε ?3 C Η Η C-H (CH2)p / \Ι 1/ \ / \ H3C C-C C-S-CH N-R3 II II \ / C-N-C C / \ II ο C-0 ο OR5 (1-8) HO Η CK3 Ο \ / I / tt η C-n. HoC—C / \Ι 1/ \ I I , H3C C-C C-S-CH N-R3 II II \ / C-N—C ΟΪ2 / \ Ο COOR5 (1-9) Table 8 Cpd.

No.

R" 8-1 a &C3. 2 8-2 a DOX 2 8-3 a Na 1 8-4 w PivO-CH9- 1 8-S a -CH90-CO- (1-Me-£Hx) 1 8-6 w P'S -CH me)0-CO-0-£Pn 1 8-7 a -CH(Me)O-CO-O-iPr 1 8-8 a -CH(Me)O-CO-O-Men 1 8-9 w W &A -CH(Me)0-CQ-0-CH9£Hx 1 8-10 W a -CH(Me)0-CO-0-£Kx 1 8 - 3.1 a -CH(Me)O-CO-cHx 1 8-12 a -CH20Ac 1 8-13 H 1-EfccOEt 1 8-14 w AA 1-PivOEt Ί oBn 8-15 a DOX Bb 8-16 «# a ΡΉ t Ή 1 8-17 Me PivO-CH2- 1 8-18 Ms -CH90-C0-(1-Me-fiHx) 1 8-19 Ma & - CH (Me) 0 - CO - 0 - £Pn I 8-20 Me -CH(Me)O-CO-O-iPr ·( 8-21 MSi & AVr» -CH(Me)0-C0-0-CH9£Hx m 1 8-22 Me -CH(Me)0-CO-0 -£,Hx Ί 8-23 Ms -CH(Ms)O-CO-£Hx 1 8-24 Ms & A^e — CH90a.c 1' 8-25 Ms 1-EtcOEt 1 «As 8-26 Ms 1-PiyOEt 1 8-27 Me Dox 1 8-28 Me Ofor'h Ab iieSVMM 1 Table 8 (cont) Cpd. r3 No. 8-29 ri Na 3 8-30 H PivO-CH2- 3 8-31 H 1-StcOEt 3 8-32 m ώΑ DOX 3 8-33 W Phth 3 8-34 IT A* PivO-CfiL- «£a 2 8-35 n 1-EtcOEt 2 labial- Cpd. No. R3 R5 9-1 H Na 9-2 H PivO-CH,- 10 9-3 H -CH90-C0-(l-Me-GHx) 9-4 H -CH2O-CO-O-Men 9-5 H -CH(Me)O-CO-£Pn 9-6 H -CH(Me)O~CO-O-iPr 9-7 H -ΟΆ(Me)O-CO-O-Men 15 9-8 H -CH (Me) O-CO-O-CH, -fiHx 9-9 H -CH(Me)O-CO-O-£Hx 9-10 H ' -CH(Me)O-CO-O£Bu 9-11 H -CH(Me)O-CO-£Hx 9-12 H 1-PivOSt 20 9-13 H -CH2OAc 9-14 H 1-EtcOEt 9-IS H -CH(Me)0-CO-0-CHEt 9 9-16 H -CH(Me)0-CO-0-CPr3 9-17 H -CH(Me)O-CO-O-£Hp 25 9 -18 H DOX 9 "19 H Phth 9-20 H Pdox 9-21 H 1- AcOEt 9-22 H 1-i.ayrOEt ' 30 9-23 H -CK90-C0~ (l-Me~£Pxi) 9-24 H 1-MecOSt 9-25 a -CH(Me)O-CO-O-Ada 9-26 Me PxvO-CKLj- 9-27 Me -CHoO-CO- (l-Me-£Hx) 35 9-28 Me -CHUfe)O-CO~O-£Pn Cpd.

No.

R3 RS 9-29 Me -CH(Me)0-CO-0-iPr 9-30 Me - CH (Me) 0 - CO - 0 - Men. 9-31 Me - CH (Me) 0 - CO - 0 - CH, - £Hx 9-32 Me -CH(Me)0-CO-0-£Hx 9-33 Me -CH(Me)O-CO-£Hx 9-34 Me -ch2oac 9-35 Me 1-EtcOEt 9-36 Me 1-PivOEt 9-37 Me DOX 9-38 Me Na 9-39 Me Phth 9-40 Ac PivO-CH,- 9-41 Ac 1-EtcOEt 9-42 AC DOX 9-43 AC Phth 9-44 Et PivO-CH2- 9-45 «5 e. &U 1-StcOEt 9-46 EC DOX 9-47 Et Na 9-48 AC Na 9-49 H -CH(Me)0-C0-0-23U 9-50 H 1-AcOEt 9-51 E - CH, O-COO- CH, - £Pr 9-52 H - CH, 0 - CO - 0 - CH, - £Bu 9-53 wr AA -CH(Me)O-CO-O-CH^-£Pn 9-54 H 2~oxo-4r5,6,7-tetrahydro1,3-benzodxoxolen-4 - yl 9-55 H ' 5-iPr-Dix-CH,- XabJ-g 9_ (conr.) Cpd. R3 R5 5 No, 9-56 H 5 - £3u - Dix - CHj - 9-57 li 1-(5-Me-Dix) Et Ί0 9-58 li 1-(XPrO-CO-O-)St S - 59 H 2-Me-l-(iPrO-CO-O-)Pr 9-60 H 2-(iPrO-CO-O-)Pr 9-61 fed AA X, " ΡχνΟΡζ* 9-62 ΪΗ 2-Me-l-PivOPr 15 9-63 K 2-PxvOPr 9-64 w 1-(1-MefiHx-CO-O-)Pr 9-65 JM 2-Me-l-(1-MefiHx-CO-O-)Pr 9-66 li 2-(1-MefiHx-CO-0-)Pr 9-67 11 1-(cHx-CO-O-)Pr 20 9-68 IT AA 2-Me-l- (fiHx-CO-O-)Pr 9-69 W AA (fiHx-AcO) -CH2- 9-70 AA 1- (fiHx-AcO) Et 9-71 H 1- (fiHx-AcO) Pr 9-72 h* A A 2 - Me -1 - (cHx- AcO) Pr 25 9-73 φφ AA 1-iByrOSt 9-74 kF 1iBvrOPr 9-75 JJ (fiPn-CO-O-)CH0- 9-76 H 1-(fiPn-CO-O-)Et 9-77 B-a AA 1-(fiPn-CO-O-)Pr 30 9-78 H 2-Me-l-(fiPn-CO-O-)Pr 9-79 K 1-AcOPr 9-80 H l-AcO-2-MePr 9-81 H PraO-CHj- 9-82 •w AA 1-Pm.OEt 35 9 - 83 H 1 - PrnOPr Table 9 .(coxx) CpcL No. R3 R5 9 " 8¾ 99 CH Ad 1-(l-Me£Pn-CO-O-)Et 9-85 99 B—3 AA l-(i-Me£Pn-CO-O-)Pr 9-86 H 2-AcOPr 9-87 H QyrO-CHj- 9-88 99 EH AA 1-ByrOEt 9-89 £* iPrO.CO.OCH,- 9-90 99 CH AA £PnO.CO.OCH2- 9-91 H £HxO.CO.OCH2- 9-92 H £BuO.CO»OCH,- 9-93 SA BuQ,CO.OCH2- 9-94 H MeO.CO.OCH2- 9-95 Me CHX.CO.OCH2- 9 - 9 6 Me £PnO.CO.OCH2- 9-97 Me £HxO.CO.OCH2- 9-98 Me iPr0.C0.0CH2- 0-00 Me iByrOCK2- 9-100 Ms A AW· 1-(iByrO)Et 9-101 Me 1-(£Pn.CO.O)St 9-102 Me £Pn.CO.OCH2- 9-103 M fiHx.CO.OCH,- Of the compounds listed above, the following are preferred, that is to say Compounds No. 9-2, 9-3, 9-5, 9-6 and 9-8, of which the following are most preferred: 9-2. Pivaloyloxymethyl 2-(2-oxo-4-pyrrolidinylthio)-6(1-hydroxyethyl) -1-methyl-1-carbapen-2 -em-3 -carboxylate, especially its pivaloyloxymethyl (IR, 5£, 6S)-2-(2-oxo4 - pyrrolidinylthio) - 6- ((IR)-1-hydroxyethyl]-1-methyl-1carbapen - 2 - em- 3 - carboxylate isomer ,10 9-3. (l-Methylcyclohexan-l-yl) carbonyloxymethyl 2- (2-oxo-4-pyrrolidinvlthio)-6-(1-hydroxyethyl)-1-methyl1-carbapen-2-em-3-carboxylate, especially its (1-methylcyclohexan-l-yl) carbonyloxymethyl (IR, 5£, 6S)-2-(2-oxo15 4-pyrrolidinylthio)-6-((Ig)-i-hydroxyethyl]-1-methyl-lcarbapen» 2 - em- 3 - carboxylate isomer,9-5. 1-(Cyclopentyloxycarbonyloxy)ethyl 2-(2-oxo-4pyrrol idinyl thio) -6- (1-hydroxyethyl) -1-methyl -1-carbapen· 2o 2-em-3-carboxylate, especially its 1-(eyelopentyloxycarbonyloxymethyl (Ig, 5£, 6£)-2-(2-oxo-4-pyrrolidinylthio) - 6-1(IR)-l-hydroxyethyl]-X-methyl-1-carbapen-2-em3- carboxylate isomer; and pharmaceutically acceptable salts thereof.

The compounds of the present invention can be prepared by a variety of methods well known for preparing this type of compound. For example, in general terms, the confounds may be prepared by reacting a compound of formula (TV) : (XV) HO H R1 \ / I C C-H / \ / \ H3C CH—CH C-R27 c COOR20 • 3. 2*7 (in which R is as defined above, R represents a group of formula -OR or -SO-R , in which: 2° R represents an alkanesulphonyl group, an arylsulphonyl group, a dialkylphosphoryl group, or a. diary lphosphoryl group; and 15 R3 represents an alkyl group, a haloalkyl group, a 2-acetylaminoethyl group, a 2-acetylaminovinyl group,- an aryl group or a heteroaryl group (i.e. an aromatic heterocyclic group); and A R represents a protecting group for a carboxylic acid) ; with a compound of formula (Vb) : ks- (ch2) 2-rXaj- (vb) TTT [in which R * represents said group of formula (III), in which, if required any active groups are protected, e_ is as defined above, and X is a balancing anion], ' to give a compound of formula (VI): HO H R1 C C-H / \ / \ H3C CH—CH C-S- (CH·?) a-Rb I I II (VI) COOR28 if required any active groups are protected, and which, if necessary contains a balancing anion], and then, if necessary, removing protecting groups and/or esterifying and/or salifying the resulting compound to give a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof.

In the above formulae, R represents: an alkanesulphonyl group, such as a aaethanesulphonyl, ethanesulphonyl, propanesulphonyl, isopropanesulphonyl or butanesulphonyl group; an arylsulphonyl group, such as a phenyl sulphonyl, tolyl sulphonyl, especially p-tolylsulphonyl, or naphthvlsulphonyl group; a dialkylphosphoryl group, such as a dimethylphosphoryl, diethylphosphoryl, dipropylphosphoryl, diisopropylphosphoryl, dibutylphosphoxyl or dipentylphosphoryl group; or a dxarylphosphoryl group, such as a diphenylphosphoryl or ditolylphosphoryl group; R represents an alkyl group, such as a methyl, ethyl, propyl or isopropyl group; a haloalkyl group, such as a fluoromethyl, chloromethyl, fluoroethyl, difluoromethyl, difluoroethyl, dichloroethyl, trifluoromethyl or trifluoroethyl group; a 2-acetylaminoethyl group; a 2-acetylaminovinyl group; an aryl group, such as a phenyl or naphthyl group which may optionally be substituted with from l to 3 substituents, which may be the same or different and examples of the substituent include the fluorine, chlorine and bromine atoms, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, nitro, hydroxy and cyano groups; a heteroaryl group such as a pyridyl or pyrimidinyl group which may optionally be substituted with from 1 to 3 substituents, which may be the same or different and examples of the substituent include the fluorine, chlorine and bromine atoms and the methyl, ethyl, propyl and isopropyl groups; and 8 R represents a protecting group for a carboxylic acid, examples of the protecting group include, for example an alkyl group such as a methyl, ethyl or t-butyl group; an aralkyl group such as a benzyl, diphenylmethyl, 4-nitrobenzyl or 2-nitrobenzyl group; an alkenyl group such as an allyl, 2-chloroallyl or 2-methylally group; a haloalkyl group such as a 2,2,2trichloroethyl, 2,2;dibromoethyl or 2,2,2-tribroraoethyl group or- a 2-trimethylsilylethyl group.

In more detail, the compounds may be prepared as illustrated in the following Methods A and B.

Method A: This is as shown in the following Reaction Scheme A: οι In the above formulae: R1, R5, Rc\ Rbe ^2θ, R29 and i are as defined above. b In Step Al of this reaction scheme, the compound of formula (Vii)t, which is the starting material, is reacted with an active derivative of an alkanesulphonic, arylsulphonic, dialkylphosphoric or diarylphosphoric . 29 acrd R~OH, e.g. an alkanesulphonic or arylsulphonic acid anhydride or a dialkylphosphoryl or diarylphosphoryl halide in the presence of a base. In Step A2, the resulting compound of formula (VIII) is then reacted without isolation with a mercaptan derivative of formula (Vb) in the presence of a base to give a compound of formula (VI) . The desired compound of formula (I) may then be prepared, if necessary, by "28 removal of the protecting group, R „ from the carboxyl group in the compound of formula (VI) . la Step Al, e^tamples of the reactive derivative of 2© the reagent of formula R OH which may be employed include: alkanesulphonic acid anhydrides, such as methanesulphonic or ethanesulphonic acid, anhydride; arylsulphonic acid anhydrides, such as benzenesulphonic or q-toluenesulphonic acid anhydride; dialkylphosphoryl halides, such as dime thy lphosphoryl or diethy lphosphoryl chloride; diarylphosphryl halides, such as diphenylphosphoryl chloride or diphenylphosphoryl bromide. Of these reagents, toluenesulphonic acid anhydride or diphenylphosphoryl chloride is preferred. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved.

Examples of suitable solvents include: halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride. 1,2-dichloroethane or chloroform; nitriles such as acetonitrile; amides such as ϋ,Η-dimethylformamide or iLH-dimethylacetamide. There is likewise no particular limitation on the nature of the base to be employed, provided that it has no adverse effect upon other parts of the molecule, particularly the A-lactam ring. Preferred bases which may be employed in this reaction include such organic bases as triethylamine, diisopropylethylamine or 4-dimethylaminopyridine.

The reaction can take place over a wide range of temperatures, and the. precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction af a relatively low temperature in order to prevent side reactions, usually at a temperature from -20^0 to 40 "3C. The time required for th® reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 10 minutes to 5 hours will usually suffice.

It is not necessary to isolate the resulting compound of formula (VIII) before the next step in the reaction scheme. . Thus, in Step &2, the reaction mixture may be treated with a mercaptan derivative of formula (Vb) in the presence off a base. The nature of the base to'be employed in the reaction is not critical but preferred bases include organic bases, such as triethylamine or diisopropylamine, and inorganic bases, ' such as potassium carbonate or sodium carbonate.

The reaction can cake place over a wide range of temperatures, and the precis® reaction temperature is not critical to the invention. In general, however, we find it best to carry out the reaction at a relatively low temperature, e.g. at a temperature from -20®C to room temperature. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 30 minutes fo 5 days will usually suffice.

After completion of the reaction, the desired compound of formula (VI) may ba recovered from the reaction mixture by conventional means, for example, onesuitable recovery procedure comprises simply distilling off the solvent from the reaction mixture. The resulting compound may be further purified, if necessary, by conventional means, for example by recrystallisation, reprecipitation or the various chromatography techniques, such as column chromatography or preparative thin layer chromatography.

If desired, before or after such further purification, the carboxy-protecting group may be removed. This is preferably effected without isolation of the compound of formula (VI) .

The fixial reaction step of process A comprises the 28 removal of the carboxy-protecting group R from the compound of formula (VI), to give the corresponding carboxylic acid of formula (I), and, if required, conversion of the resulting free acid to another salt or ester. This step is optional, and it will be appreciated that the removal of the carboxy-protecting group may not always be necessary or desired, for example when the compound of formula (VI) is a pharmaceutically acceptable ester within the scope of the present invention. -If it is desired to remove the carboxy-protecting group, this may be done by the use of conventional methods, the choice of which will depend upon tne nature of the protecting group employed.

Ie the protecting group is removable by reduction, ror example if it is -a haloalkyl group, an aralkyl group or a benzhydryl group, it may be removed by contact with a reducing agent. In the case of haloalkyl groups, such as the 2,2-dibromoethyl or 2,2,2-trichloroethyl groups, the preferred reducing agent is a combination of zinc with acetic acid. If the protecting group is an aralkyl group (such as a benzyl or nitrobenzyl group) or a benzhydryl group, it is preferred to remove it either by catalytic reduction using hydrogen and a suitable catalyst, such as platinum or palladium on carbon; or by reduction, with an alkali metal sulphide, such as sodium sulphide or potassium sulphide. Whatever the reduction technique, the reduction process is preferably effected in the presence of a solvent, the nature of which is not critical, provided that it has no adverse effect upon the reaction. Suitable solvents include alcohols (such as methanol or ethanol) , ethers (such as tetrahydrofuran or dioxane), aliphatic carboxylic acids (such as acetic acid) , or a mixture of one or more of these organic solvents with water. The reaction temperature is not critical but will normally be in the range from 0°C to room temperature. The time required for the reaction will vary, depending upon the nature of the starting materials and reducing agents, as well as upon the reaction temperature, but a period of from 5 minutes to 12 hours will normally sufficeAfter completion of the reaction, the desired compound, which will contain a free carboxy group, may be recovered by conventional means from the reaction mixture. For example, a suitable recovery technique comprises: separating off any insolubles; and then distilling off the solvent to give the desired product.

Thxs may, if necessary, be further purified by conventxonal means, for example recrystallization or the varxous chromatography techniques, such as preparative tnxn layer chromatography or column chromatography.

If desired, a carboxy group in the compound prepared as described above can be converted to an ester group hydrolysable under physiological conditions. This may s be effected by conventional means. If R represents an ester which is hydrolysable under physiological conditions, e.g. a pivaloyloxymethyl, acet oxyme thyl, phthalidyl, indanyl, methoxymethyl or 2-0X0-5-methyl-1,3-dioxolen-4-ylmethyl group, the confounds of formula (I) can be hydrolyzed in vivo under physiological conditions. Accordingly such a compound may be administered directly to a patient without deprotection.

This is as shown in the following Reaction Scheme 3: 4Λ In the above formulae R1, Ra, Rb, R28, 23° and x are as defined above.

The compounds of formula (IX) used as starting materials in this reaction scheme can be prepared as described in Japanese Patent Application Kokai No. Sho 62-30781.

In Step Bl, the compound of formula (VI) can be prepared by reacting a compound of formula (IX) with a mercaptan compound of formula (Vb) ia the presence of a base and in an inert solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction j 5 or on the-reagents involved. Examples of suitable solvents include: ethers, such'as tetrahydrofuran; nitriles, such as acetonitrile; fatty acid amides, such as dimethylformamide; sulphoxides, such as dimethyl sulphoxide; water; or a mixture of any two or more 2Q thereof. The base used in the reaction is likewise not critical, provided that it does not affect other parts of the molecule, particularly the A-lactam ring.

Examples of suitable bases include; organic bases, such as diisopropylethylamine, triethylamine, E-methylpiperidine or 4-(g,g-dimethylamino)pyridine; and inorganic bases, particularly alkali metal carbonates, such as potassium carbonate or sodium bicarbonate. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention, although we prefer that the reaction is carried out at relatively low? temperature in order to prevent side reactions. In 'general, we find it convenient to carry out the reaction at a teaperature from -20®C to 40®C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, provided chat the reaction is effected under the preferred conditions outlined above, a period of from 5 minutes to 5 days will usually suffice.

After completion of the reaction, the desired compound of formula (VI) can he recovered from the reaction mixture hy conventional means. Also, the compounds of formula (I) can, if necessary, toe prepared toy deprotection of a compound of formula (vi) using the procedure described in Method Ά. Further separation and purification of the resulting compound may he effected as described in Method A.

Compounds of formula (Vb), which are also starting materials in the above reaction schemes may be obtained by conventional and well known means for preparing this type of compound . In the case of those compounds of formula (Vb), where these are not otherwise available, they may be prepared as follows: First, a compound of formula (Z): L-RC (X) [in which L represents a leaving group, such as a hydroxy group, a halogen atom (such as a chlorine, bromine or iodine atom) or a sulphonyl oxy group (e.g. a methanesulphoxxyloxy, propanesulphonyloxy, trifluoromethanesulphonyloxy or toluenesulphonyloxy group) and R.c represents a 2-oxopyrrol idinyl group, as defined in relation to the group of formula (1ΪΙ1Ϊ is converted to the corresponding protected thio conmound of formula (XI) : (XI) (in which R° represents a thio-protecting group such as an alkanoyl group (e.g. an acetyl or propionyl group) or an aralkyl group (e.g. a 4-raethoxybenzyl, 3,4-dimethoxybenzyl, benzhydryl, triphenylmethyl or di(4-methoxyphenyl)methyl group)].

Wien 1« represents a hydroxy group, this may be performed by means of the Mitsunobu reaction, which may be performed under conditions known per se, in the presence of diethyl azodicarboxylate, triphenyl phosphine and thioacetic acid.

When L represents 'a halogen atom or a sulphonyloxy group, the reaction may be performed by reacting the compound of formula (X) with a sodium or potassium salt of Rd-SH.

The second step is a conventional hydrolysis reaction and may be performed under conditions known per ’ Γτί se. For example, when R is an alkanoyl group, it may be removed under alkaline or acidic conditions, for example, with sodium hydroxide in aqueous methanol.

When Ru is an aralkyl group, it may be removed, e.g. with trifluoromethanesulphonic acid in the presence of trifluoroacetic acid and anisole.

The compounds of the present invention exhibit outstanding antibacterial activity with a wide spectrum of activity, and they are. also resistant to ?-lactamase. As assessed by the agar plate dilution method, they have been shown to be active against a wide range of pathogenic microorganisms, including both Gram-positive bacteria (such as staphylococcus. aureus and Bacillus subtilis) and Gram»negative bacteria, (such as Escherichia coli., Shigella flexaeri., Klebsiella pneumoniae. Proteus vulggria, Sfisxatia species e.g. S&rratia masSsSSSSS, BntexoJ^Xgr species e.g. Enterobacter cloacae, SaJjaQGSllsL gnterif idlg, and Eassitoosaa a&Eugisos^) and are thus very useful for the treatment of diseases caused by such microorganisms in humans and non-human animals. Whereas thienamycin and its analogs are inactivated jn vivo in mammals by dehydropeptidase I, the compounds of the invention are much more stable to this enzyme and exhibit good urinary recovery, and thus possess good biological activity.

They also exhibit low toxicity when tested in laboratory an ί mg 1 %.

Table 10 sets out the activities of a compound of the present invention against various bacteria, in terms of their minimal inhibitory concentrations (ug/ml) .

J£a£>XSL_lG Microorganism Cpd of Example_A@ ,C 0.01* 0.01* 25 A: 209 B: Becheri-chi-a ssXi mihj n&S. aeruginosa 1001 0.01*: no higher than 0.01 The results given above indicate chat the compounds of the present invention may be used to treat or prevent diseases caused by a wide range of pathogenic bacteria.

The esters produced as described in Examples 39, 40 and 41 were incubated at 37°C for 1 hour with horse serum, alter which the MIC values were determined. The values were all exactly the same as those of Example 36 and reported above. This means that the esters are easily cleaved by the esterase in the small intestines, after they have been orally administered, and that they are thus absorbed well through the digestive tracts, and exhibit in full the activity possessed by the free acid.

The compounds of the invention may be administered either orally or parenterally for the treatment of diseases in humans and other animals caused by pathogenic microorganisms. The compounds may be formulated into any conventional forms for administration. For example, for oral administration, suitable formulations include tablets, granules, capsules, powders and syrups, whilst formulations for parenteral administration include injectable solutions for intramuscular or, more preferably intravenous, injection.

The compounds of the invention are preferablyadministered parenterally, particularly ia the form of an intravenous injection.

The dose of the compound of the invention will vary, depending upon the age, body weight and condition of the patient, as well as upon the form and times of administration- However, in general the adult daily dose is expected to be from 100 to 3000 mg of the compound, which may be administered in a single dose or in divided doses.

SMPL&_33 gfidim,,JJ.R, 5_··2-(2xgxQ-L^nyx^JJ JLUairAnMsggsyethyl 1 -1-methyls!-carbaoen-2 - em- 3 5 Si^bQxylatg 126 μί of diisopropylethylamine and 150 μ a of diphenylphosphoryl chloride were added,, whilst stirring and ice-cooling, to a solution of 250 mg of 4-nitro10 benzyl (IR, 5R, SS)-[(IE)"l"hydroxyethyll-l-methyl-2oxo-x-carbapenam-3-carboxylate in 3 ml of dry acetonitrile, and then the mixture was stirred at 0 - 5°C for 1 hour. At the end of this time, 288 μ of diisopropylethylamine and a solution of 222 mg of a 1 : l by weight mixture of 3-mercapto-2-pyrrolidinone (prepared by a similar process to that described in Preparation 19) and trifluoromethanesulphonic acid in 2 ml of acetonitrile were added, with ice-cooling, to the previous reaction mixture. The whole mixture was then allowed to stand for 3 days ia a refrigerator. Ac the end of this time, the mixture was diluted with ethyl acetate, washed, in turn, with an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulphate. The solvent was then distilled off under reduced pressure to leave a crude product, which was dissolved ia a mixture of 20 ml of tetrahydrofuran and 20 ml of a 0.1Ϊ4 phosphate buffer solution (pH 7.1),, and then hydrogenated ac room temperature for 2 hours in the presence of 331 mg of 10% -w/w palladium-on-charcoal. At the end of this period, insoluble matter was removed by filtration using a Celite filter aid and the filtrate was washed with diethyl ether. The aqueous phase was concentrated by evaporation under reduced pressure,, and the residue was subjected to column chromatography through Diaion HP-20AG, eluted with water. The eluate was concentrated by evaporation under reduced pressure and then lyophilized to give a crude product. This was further purxtied hy Lobar column chromatography (Merck, Lichroprep RP-θ, size B), eluted with a 3% by volume aqueous methanol solution. The eluate was concentrated by evaporation under reduced pressure and lyophilized to give 35 mg of the title compound in the form of a colourless powder.

Ultraviolet Absorption Spectrum (H9O) λnm: 302.

Nuclear Magnetic Resonance Spectrum (D^O, 270 MHz) δ ppm: 1.00 (3H, doublet, J » 7.33 Hz); 1.11 (3H, doublet, J « 6.60Hz); 1.86 - 1.98 (IH, multiplet); 2.40 - 2.55 (IH, multiplet); 3.18 - 3.39 (4H, multiplet); 3.71 (IH, doublet of dooublets, J « 9.16 & 6.60 Hz); 4.02 - 4.12 (2H, multiplet).

EXAMPLE. 34 god-to J IB·.,. JSSx^g-) .^.2^(.2 -pjcpTf.ULW J-_- hydrcayethyli^i--met.byJ.-C.arbap.^^--^«i· l-^rfioxylate 126 μ a of diisopropylethylamine and 150 μβ of diphenylphosphoryl chloride were added, whilst stirring and ice-cooling, to a solution of 250 mg of 4-nitrobenzyl (lg, SS, 6S) - ((lg)-l-hydroxyethyl]-1methyl-2-oxo-1-earbapenam-3-carboxylate in 5 mi of dry acetonitrile, and then the mixture was stirred at 0 - 5®C for 1 'hour. At the end of this time, 144 μ a of diisopropyl©thylamine and 97 mg of 4-mercapto2-pyrrolidinone (prepared as described in Preparation 20) were added, with ice-cooling, to the previous reaction mixture. The whole mixture was then stirred at 0 - 5eC for 7 hours and then allowed to stand overnight in a .refrigerator. At the end of this time, the mixture was diluted with ethyl acetate, washed twice with an aqueous solution, of sodium chloride, and then dried over anhydrous magnesium sulphate. The solvent was then distilled off under reduced pressure to leave a crude product, which was dissolved in a mixture of 20 ml of tetrahydrofuran and 20 ml of a 0.1M phosphate buffer solution (pH 7.1), and then hydrogenated at room temperature for 2.5 hours in the presence of 33Γ mg of % w/w palladium-on-charcoal- At the end of this time, insoluble matter was removed by filtration using a Celite filter aid and the filtrate was washed with diethyl ether. The aqueous phase was concentrated by evaporation under reduced pressure, and the residue was subjected co column chromatography through Diaion HP-20AG, eluted with water. The eluate was concentrated by evaporation under reduced pressure and then lyophilized to give a crude product. This was further purified by Lobar column chromatography (Merck, LiChroprep RP-8, size Β) , eluted 'with a 3% by volume aqueous methanol solution. The eluate was concentrated by evaporation under reduced pressure and lyophilised co give 91 mg of the title compound in the form of a colourless powder. This is a mixture of the two isomers in respect of the carbon atom at the 4-position of the pyrrolidine ring, ia proportions of about l : l.B Ultraviolet Absorption Spectrum (H90) x^_,y - nm: 300.

Nuclear Magnetic Resonance Spectrum (D90, 270 MHz) δ ppm: 1.02 & 1.03 (3H, doublet x2, J «7.33 & 6.96 Hz); 1.10 (3H„ doublet, J - 6.60 Hz); 2.12 & 2.22 (IH, doublet of doublets x 2, J « 17.59 & 4.40 Kz and 17.59 & 4.03 Hz); 2.74 & 2.77 (IH, doublet of doublets x 2, J « 17.59 & 9.16 Hz and 17.59 & 9.16 Hz); 07 • 3.29 (3H 64 • 3.73 (IH 84 • 3.96 (IH 00 • 4.12 (2H multiplet); multiplet); multiplet); multiplet).

E3CM>LE_15 5zjSas£M8^-oxo-.l,3-dioxolen-4rylmethyl (IR, 55,. .65)-2IZzi3^ar3xrPy^rol jdlnyU:b.lo) -6-((IR) -1-hvdroxvethyn -laig-thvl Ircarbapen - 2 - em- 3-- carboagglate A solution of 66 mg of 5-methyl-2-oxo-1,3-dioxolen4-ylmethyl iodide (prepared by heating 5-methyl-2-oxo1,3-dioxolen-4-ylmethyl bromide and sodium iodide under reflux in acetone) in chloroform was added to a mixture of 47.6 mg of sodium (IB, 55., 6£)-2-(2-oxo-3pyrrolidinylthio)-6-[(IR)-1-hydroxyethyl]-l-methyl-lcarbapen-2-em-3-carboxylate and 0.4 ml of dry dimethylformamide. The mixture was stirred at room temperature for 80 minutes and then at 30 - 45°C for 4.5 hours. At the end of this time, the reaction mixture was diluted with ethyl acetate and washed four times with an aqueous solution of sodium chloride. The extract was dried and the solvent was distilled off under reduced pressure. The residue was purified by Lobar column chromatography (Merck, LiChroprep Si60, size A), eluted with a 10 ; l by volume mixture of ethyl acetate and methanol, to give 27.4 mg of the title compound In the form of a colourless powder.

Ultraviolet Absorption Spectrum (CH^OK) nm: 322.

Nuclear Magnetic Resonance Spectrum (hexadeuterated dimethyl sulphoxide, 270 MHz) 5ppm: 1.13 (3K, doublet, J - 7.32 Hz); 1.15 (3H, doublet, J - 6.35 Hz); I»84 - 1.98 (1H, multiplet); 2.17 (3H„ singlet); 2.50 - 2.65 (1H, multiplet); 3.12 - 3.45 (4H, multiplet); 3.77 - 4.os (2H, multiplet); 4.14 (XH, doublet of doublets, J = 9.27 & 2.44 Hz); 5.0Θ (2H, singlet).

SMLU6 Sodium (l.K,_5S, 65) -2- (2-oxo-4-ovrrolidinylthio) -6L( iRl^irhydroxyethvl 1 -1-methvl-1 - carbapen-2^em.- 3 carboxylate 1.45 ml of diisopropylethylamine and 1.70 ml of diphenyiphosphoryl chloride were added, whilst ice-cooling, to a solution of 2.93 g of 4-nitrobenzyl (IR, 5R, 6S.) -6- [ (lg) -l-hydroxyethyl] -1-methyl-2-oxo-1carbapexiam-3 - carboxylate in SO ml of dry acetonitrile, •^q and then the mixture was stirred at 0 - 5°C for 30 minutes. 1.45 ml of diisopropylethylamine and a solution of 1.35 g of 4-mercapto-2-pyrrolidinone (prepared as described' in Preparation 20) in 5 ml of acetonitrile were added to the mixture, cooled at -20°C, and then the whole mixture was stirred at 0°C for 3 hours, after which it was allowed to stand at the same temperature overnight. The reaction mixture was then diluted with ethyl acetate, washed twice with an aqueous solution of sodium chloride and filtered. The organic phase was dried over anhydrous sodium sulphate and the solvent was distilled off under reduced pressure' to give the 4-nitrobenzyl ester of the title compound as a foam. This was dissolved in 150 ml of tetrahydrofuran and the- solution was filtered to remove insoluble matter. ISO ml of a 0.1M phosphate buffer solution (pH 7.1) were added to the filtrate and catalytic reduction was effected at room temperature for 2.5 hours in the presence of 1.5 g Of w/w palladium-on- charcoal.

The reaction mixture was then worked up in a similar manner to that described in Example 34, to give 1.05 g of the title compound as a colourless powder. This is a mixture of the two isomers in respect of the carbon atom at the 4-position of the pyrrolidine ring, in proportions of about 9:1.

Ultraviolet Absorption Spectrum (Η^,Ο) nm: 299.

Infrared Absorption Spectrum (KBr) vniax cm" 1748, 1689, 1597, 1393, 1296.

Nuclear Magnetic Resonance Spectrum (D^Oe 270 MHz) δ ppm.: 1.03 (3H, doublet, J « 7.3 Hz); 1.10 (3H, doublet, J « 6.2 Hz); 2.12 (0.9H, doublet of doublets, u « 17.9 & 4.4 Hz); 2.22 (0.1H, doublet of doublets, J - 17.9 & 4.4 Hz); 2.74, 2.77 (lH, 2 x doublet of doublets, J = 17.9 & 8.4 Hs); 3.08 - 3.24 (2H, multiplet); 3.26 (1H, doublet of doublets, J - 5.9 & 2.6 Hz); 3.69 (1H, doublet of doublets, J - 11.4 & 6.6 Hz); 3.84 - 3.93 (1H, multiplet); 4.02 - 4.11 (2H, multiplet).

Sodium. (IR. 55.-, ^S)-2-J2-oxor4rpyxcaliaihvlthiQjL··^.

. (,( IR) -.1 - hvdraxy_ex.hyll^-lr-methyl -I- caxfeaPfiazZxgBnlz A crude s-nxtrobenzyl ester of the title compound was prepared, following substantially the same procedure as described in Example 36 above but using 330 mg of 4-nitrobenzyl (l£, SB, 6S)-6-[(lg)-1-hydroxyethyl] 51 1-methyl-2-oxo-l-carbapenam-3-carboxylate. The ester was subjected to column chromatography through 50 g of silica gel, eluted with a 4 : 1 by volume mixture of ethyl acetate and methanol. The eluent was concentrated by evaporation under reduced pressure to give 260 mg of a colourless powder, which was mixed with 10 ml of ethyl acetate. This mixture was ice-cooled and filtered to remove insoluble matter. The filtrate was concentrated by evaporation under reduced pressure, and diisopropyl ether was added to the residue to give a precipitate. This was collected by filtration and dried to give 150 mg of the p-nitrobenzyl ester of the title compound as a powder which is either the g.- or the §.- isomer in respect of the carbon atom at the 4-position of the pyrrolidine ring.

Nuclear Magnetic Resonance Spectrum (hexadeucerated dimethyl sulphoxide, 270 MHz) δppm: I. IS 1.18 2.02 (3H, doublet, u (3H, doublet, J « 6.0 Hz); 7.3 HZ); (IH, doublet of doublets, 2.72 (IH, doublet of doublets, 3.12 - 3.48 (3H, multiplet); 3.74 (IH, doublet of doublets, 3.94 - 4.05 (2H, multiplet); 4.24 (IH, doublet of doublets, 5.06 (IH, doublet, J - 4.9 Hz); 5.30, 5.46 (2E, AB, J - 14.2 Hz) 7.71 (2H, doublet, J - 0.8 Hz),8.23 (2H, doublet, u - 0.8 Hz).

J - 17.1 & 4.9 Hz) ; J - 17.1 & 8.3 Hz); .7 & 5.3 Hz) J - 9.8 & 2.9 Hz); 100 mg of the p-aitrobenzyl ester obtained In the previous step were subjected to catalytic hydrogenation in a similar manner to that described in Example 34, co give 55 mg of the title compound having either the g- or the a-configuration, in respect of the carbon atom at the 4-position of the pyrrolidine ring, in a pure state 5Z as a powder.

Ultraviolet Absorption Spectrum nm: 299 (K^O) .

Nuclear Magnetic Resonance Spectrum (D^O, 270 MHz) δ ppm: 1.03 (3H„ doublet, J = 7.3 Hz); 1.10 (3H, doublet, J = 6.2 Hz); 2.12 (IH, doublet of doublets, J 2.74 (IH, doublet of doublets, J 3.08 - 3.24 (2H, multiplet);. 3.26 (IH, doublet of doublets, J 3.69 (IH, doublet' of doublets, J 3.84 - 3.93 (IH, multiplet); 4.02 - 4.11 (2H, multiplet). 17.9 & 4.4 Hz); 17.9 & 8.4 Hz); 5.9 & 2.6 Hz); 11.4 & 6.6 Hz); Sodium, (IR, 5S, 6S) -2~ (2-oxo^pyrrolidinylthxo) -6-LURj - I,-hydroxyethyl 1 -1 -methyl,-l-carbapen-2-em-J_carboxylaxe A crude p-nitrobenzyl ester of the title compound was prepared, following substantially the same procedure as that described in Example 34, but using 300 mg of 4-nitrobensyl (lg, 5g, 6g) -6- [ (lg) -1-hydroxyethyl) 1-methyl-2-oxo-l-carbapenam-3-carboxylate. The ester was subjected to column chromatography through 50 g of silica gel, eluted with a 4 : 1 by volume mixture of ethyl acetate and methanol. The eluent was concentrated by evaporation under reduced pressure to give 270 mg of a colourless powder.. The product is about a 1 : 1 mixture of the two isomers in respect of the carbon atom at the 4-position of the pyrrolidine ring. 100 mg of this product were mixed with 10 ml of ethyl acetate.

The mixture was filtered to collect the insoluble matter, which was recrystallized from a mixture of methanol and isopropanol to give 30 mg of the p-mtrobenzyi ester of the title compound as colourless needles. This is either the B or the £-isomer in respect of the carbon atom at the 4-position of the pyrrolidine ring and is the other isomer having the opposite configuration of the compound obtained in the first step of Example 37.

Nuclear Magnetic Resonance Spectrum (hexadeuterated dimethyl sulphoxide, 270 MHz) 6ppm: 1.16 (3H, doublet, J » 6.3 Hz); 1.17 (3H, doublet, J « 7.3 Hs); 2.13 (IE, doublet of doublets, j - 17.1 & 4.4 Hz); 2.79 (IH, doublet of doublets, J « 17.1 & 7.8 HZ); 15 3.10 (TH, doublet of doublets, J *' 10.8, 3.4 Hz); 3.16 - 3.35 (IH, multiplet); 3.40 - 3.51 (IH, multiplet); 3.70 (IH, doublet of doublets, J « 10.7 & 7.3 Hz); 3.95 - 4.12 (2H, multiplet); 4.25 (IH, doublet of doublets, J - 9.3 & 2.5 Hz); .07 (IH, doublet, J - 5.4 Hz); .30,. 5.46 (2H, AB, J ~ 14.2 Hz); 7.71 (2H, doublet, J - 8.8 Hz); 8.23 (2H, doublet, J - 8.8 Hz). stg of the p-nitrobenzyl ester obtained in the previous step were subjected to catalytic hydrogenation in a similar manner to chat'described ia Example 34, co give ii mg of the title compound having either the R- or the S-configuration, in respect of the carbon atom at the 4-position of the pyrrolidine ring and having the opposite configuration to that obtained in Example 37, in a pure state as a powder.

Nuclear Magnetic Resonance Spectrum (D20, 270 MKz) δ ppm: 1.02 (3H, doublet, J - 7.3 Hs) ; OH, doublet, J « 6.6 Hz) 22 (1H, doublet of doublets. J «= 17.6 & 4.4 Hz) 77 (1H, doublet of doublets, J « 17.6 & 8.4 Hz) 08 - 3.25 (2H, multiplet); 25 (1H, doublet of doublets, J = 5.9 & 2 .6 Hz); 68 (1H, doublet of doublets, U 1=: 11.4 & 6.4 Hz) 84 - 3.96 (1H, multiplet); 00 - 4.12 (2H, multiplet). t hvl Jig^S.§., ),-2^12-QXQrArpyscgiidiayl thioi^s- r (lR)..-l.-hvdroxyethyl1. •.l-methvl-l-carbanen-S-em-3,-carboxylate 100 mg of sodium 2-(2-oxo-4-pyrrolidinylthio)6- ί (IS.) 1 -hydroxyethyl3 -1-methyl-l-carbapen-2~em-3carboxylate obtained by a similar procedure to that described in Example 36 were suspended in 3 ml of dry W,N-dimethylacetamide. 80 μ?, of pivaloyloxymethyl iodide were added, whilst ice-cooling, to the suspension, and then the mixture was stirred for 15 minutes, during which time the mixture became a solution. The reaction mixture was then diluted with 50 ml of ethyl acetate and washed twice with an aqueous solution of sodium chloride. The organic phase was dried over anhydrous sodium sulphate and the solvent was distilled off under reduced pressure. The residue was purified by Lobar column chromatography (Merck, LiChroprep RP-8, size B), eluted with 60% by volume aqueous methanol. The eluent was evaporated under reduced pressure to remove the methanol, leaving the aqueous phase, which was mixed with sodium chloride and then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulphate and concentrated by evaporation under reduced pressure to give 110 mg of the title compound as a colourless powder.

Ultraviolet Absorotion Spectrum (CH.CN) λ nm: 323 (c - 10760).

Infrared Absorption Spectrum (KBr) v cm1: 1778, 1756, 1699.

Nuclear Magnetic Resonance Spectrum (CDCs^, 270 MHz) δ ppm; 1.23 (9H, singlet) ; 1.29 (3H, doublet, J « 7.3 Hz) ; 1.35 (3H, doublet, J - 6.2 Hs) ; 1.95 (IH, broad singlet); 2.33 (IH, doublet of doublets, J 2.79 (IH, doublet of doublets, J 3.22 -3.34 (2H, multiplet); 3.38 (IH, doublet of doublets, J 3.80 (IH, doublet of doublets, J 3.95 - 4.05 (IH, multiplet); 4.20 - 4.27 (2H, multiplet); .79 (IH, broad singlet); .83, 5.97 (2H, .AB, J - 5.5 Hz). 17.6 & 6.2 Hz); 17.6 & 8.8 Hz); 9.9 & 4.8 HZ); 10.3 & 7.0 Hz); BXAMPJlS.-AQ .(.1 -MethylcvclQhexan-1 - vl, .ItLarbonvlo^naexhy^U.R 8. JS.._6g) 2 - .(2 - qxq-. 4 - pyrrol .idinvlt hio) _6-inRJ^ihydrQ?org£hylX- .1^ methyl -1 -.carbapen.c2^_em- 3. ^arhoxylats .Following a similar procedure to that described In Example 39, but using (l-methylcyclohexan-l-yl) carbonyloxymethyl Iodide in place of pivaloyloxymethyl iodide, the title compound was obtained.

Ultraviolet Absorption Spectrum (CH^CN) 323 (e - 9655). nm: — Ί Znrrared Absorption Spectrum (KBr) v cm "s 1777, 1753, 1700.

Nuclear Magnetic Resonance Spectrum (CDCs3, 270 MHz) δ ppm: 1.18 (3H, singlet); 1.29 (3H, doublet, J « 7.3 Hz); 1.35 (3H, doublet, J « 6.2 Hz); 1.25 - 1.75 (9H, multiplet); 2.00 - 2.00 (2H, multiplet); 2.33 (1H, doublet of doublets, J 2.79 (1H, doublet of doublets, J 3.21 - 3.33 (2H, multiplet); 3.38 (1H, doublet of doublets,, J 3.79 (1H, doublet of doublets, J 3.95 " 4,05 (IB, multiplet); 4.21 - 4.30 (2H, multiplet); .70 (1H, broad singlet); .87, 5.96 (2H, AB, J « 5.5 Hz). 17.6 & 6.2 Hz) ; 17.6 & 8.8 Ha); 9.9 & 4.8 Hz); 9.9& 7.0 Hz); EXAMPLSLAI 1_ (Cvclpheptyl^cvcarbonyloxvlethyl_ UR,.. S^_6S) -2- (,2.-oxo^ 4 - pyrrol idinylthio)_ -_6r. [_(ISi --i.-hydrQxyexhyiJ ~ Vmethyl^i.-. gjarbaaghcB Following a procedure similar to that described in Example 39, but using 54 mg of sodium 2-(2-oxo-4pyrrolidinylthio) -6- [(IB) -l-hydroxyethyl] -l-methyl-130 carbapen-2-em-3-carboxylate obtained by a similar procedure to that described in Example 36 and SO μ® of 1-(cyclohexyloxycarbonyloxy)ethyl iodide, 62 mg of the title compound were obtained as a colourless powder. ultraviolet Absorption Spectrum (CK^CN) 323 (ε « 10766).

Inf reared Absorption Spectrum (KBr) v cm 1759, 1701. - ~ Nuclear Magnetic Resonance Spectrum (CDC«3, 270 MHz) δ ppm: 1.28 (3H, doublet, J « 7.0 Hz) ; 1.33, 1.36 (3H, two doublets, J « 6.2 Hz); 1.59, 1.61 (3H, two doublets, J « 5.5 Hz); 1.2 - 1.6 (SH, multiplet); 1.7 - 2.0 (5H, multiplet); 2.33 (IH, doublet of doublets, J « 17.6 & 6.2 Hz) ; 2.79' (IH, doublet of doublets, J « 17.6 & 8.8 Hz) ; 3.24 - 3.33 (2H, multiplet); 3.35 - 3.42 (IH, multiplet); 3.76 - 3.85 (IH, multiplet)? 3.94 - 4.05 (IH, multiplet); 4.19 - 4.27 (2H, multiplet); 4.59 - 4.70 (IH, multiplet); .69 (IH, broad singlet); 6.88 (IH, quartet, J «5.5 Hz).

E3CSMgLE.41 i^.lgvgldpentvl.oxvcarbonyl.oyyl-e.t-hyi—.(IR,- _S.S^_. SSL- kJ 2^ oxo - 4 - pyrrol idinylthi b) -6-f (1R1-1-hydrpxyetliyilrlr methyl -1 - ca.rba.oen- 2 - em- 3 - C-arboxy.la.te.

Following a procedure similar to that described in Exaamle 39, but using 1-(cyclopentyloxycarbonyloxy) ethyl iodide, th© title compound was obtained.

Ultraviolet Absorption Spectrum (CH3CN) nm: 322 (e « 10651).

Infrared Absorption Spectrum (KBr) vn,gy cm : 1760, 1701.

Nuclear Magnetic Resonance Spectrum (CDCa^, 270 MHz) ppm: 1.28, 1.29 (3H, two doublets, J - 7.3 Hz) ; 1.33, 1.35 (3H, two doublets, J » 6.2 Hz) ; 1.58, 1.60 (3H, two doublets, j = 5.5 Hz) ; 1.65 - 1.95 (8H„ multiplet); 2.33 (XH, doublet of doublets, J « 17.6 & 6.2 Hz); 2.79 (1H, doublet of doublets, J - 17.6 & 8.8 Hz); 3.23 - 3.32 (2H„ multiplet); 3.38, 3.39 (IK, two doublet of doublets, J = 9.9 & 4.8 Kz); 3.68 - 3.87 (1H, multiplet); 3.96 - 4.07 (1H, multiplet); 4.19 - 4.27 (2H, multiplet); .08 - 5.16(1H, multiplet); .66 (1H, broad singlet); 6.87 (1H, quartet, J - 5.5 Hz). -(2 -.oxo - 4_-pyrrQl_idiny_lthjQj -6 r_t (IB).- 3·^ΜΓΟ3Ε^&£^ν11^ lrme^ylrV.^£fe^hr2r-pm-^-c^rbj?xvAa^ Following a procedure similar to that described in Example 39, but using 1- (cyclohexylmethyloxycarbohyloxy)ethyl iodide, the title compound was obtained.

Ultraviolet Absorption Spectrum (CELLOS) nm: 323 (e - 10975).

Infrared Absorption Spectrum (KBr) caa 1766, 1700, 1269.

Nuclear Magnetic Resonance Spectrum (CDCa3, 270 MHz) 6ppm: 0.95 - 1.26 (5H, multiplet); 1.28, 1.29 (3H, two doublets, u - 7.3 Hz) ; 1.33, 1.35 (3H, two doublets, u . 6.2 Hz) ; 1.59, i.Sl (3H, two doublets, iT ra S.9 & 5.5 1.64 - 1.76 (SH, multiplet); 1.87 (IH, broad singlet); Hz) ; 2.33 2.79 3.24 3.37 3.75 3.95 4.20 .73 6.86, (IH, doublet of doublets, J (IH, doublet of doublets, J - 3.35 (2H, multiplet); - 3.42 (IH, multiplet); - 3.87 (IH, multiplet); - 4.06 (3H, multiplet); - 4.28 (2H, multiplet); (IH, broad singlet); 6.87 (IH, two quartets, J 17.6 & 6.2 Hz) ; 17.6 & 8.8 Hz) ; .9 & 5.5 Hz). 1-(Isopropoxycarbonvloxy)ethyl_(lR, 5S, _6S) -2- (2-oxo^ 4-pyrrolidinylthio)-6-f(IR)-l-hvdrpxyetbyll-1-methyl1-carbapen-2-em-3 -carboxylate Following a procedure similar to that described in Example 39, but using 1-(isopropoxycarbonyloxy)ethyl iodide, the title compound was obtained.

Ultraviolet Absorption Spectrum (CH^CNj nm: 323 (e « 10961).

Infrared Absorption Spectrum (KBr) v cm1: - ** 1762, 1701, 1272.

Nuclear Magnetic Resonance Spectrum (CDCs^, 270 MHz) 6ppm: 1.26 - 1.36 (12H, multiplet); 1.59, 1.61 (3H, two doublets, J - 5.5 Hz); 1.80 (IH, broad triplet, J « 3.7 Hz); 2.33 (IH, doublet of doublets, J - 17.6 & 6.2 Hz); 2.79 (IH, doublet of doublets, J «= 17.6 & 8.8 Hz); 3.24 - 3.34 (2H, multiplet); 3.35 - 3.42 (IH, multiplet); 3.76 - 3.87 (IH, multiplet); 3.95 - 4.07 (IK, multiplet); 4.19 - 4.28 (2H, multiplet); 4.82 - 4.99 (IH, multiplet); S.63 (IH, broad singlet); 6.88 (IH, quartet, u « 5.5 Hz).

(IR, 2S_,__5R) -(a) -Menthvloxv-carbonvloxymethyl lXR,_5S,._6SJ^^(.2-oxo-4-oyrrQli Following a procedure similar to that described in Example 39, but using (IR, 2S, SB)- (s)-menthyloxycarbonyloxymethyl iodide, the title compound was obtained.

Ultraviolet Absorption Spectrum (CBLCN) nm; □ Π15μι€ 324 (ε = 10801). infrared Absorption Spectmn (KBr) cm'1: 1763, 1695, 1266.

Nuclear Magnetic Resonance Spectrum (CDC«3, 270 MHz) δ ppm; 78 (3H, doublet, σ « 7.0 Hz) ; 89 (3H, doublet, j 7.0 Hz) ; 92 (3K,. doubletι σ at! 7.3 Hz); 29 (3H, doublet. j w; 7.3 Hz) ; 35 (3H, doublet, σ . 6.2 Hz) ,- 0.9S - 1.55 (.SH, multiplet); 35 1.63 - 1.73 (2K, multiplet); 1.88 - 2.03 (IH, multiplet); 2.08 - 2.17 (IH, multiplet) ,- 2.34 (IH, doublet of doublets, J «= 17.2 & 6.2 Hz); 2.79 (IH, doublet of doublets, J = 17.2 & 8.8 Hs); 3.22 - 3.34 (2H, multiplet); 3.39 (IH, doublet of doublets, J " 9.5 & 4.8 Hs); 3.74 - 3.86 (IH, multiplet); 3.96 - 4.06 (IH, multiplet); 4.18 - 4.28 (2H, multiplet); 4.56 (IH, doublet of triplets, J « 10.6 & 4.4 Hz); 5.70 (IH, broad singlet) ,- 5.89, 5.91 (2H, AB, J « 5.9 Hz). ΕΧΑΜΡΒΕ 46.

-Methyl-2-oxo-1., 3 -dioxolen-4-ylmefchvl (1R,_.55,.„6£1^ 2-(2 r oxo - 4 -p.yrrol_idlnvl thiol - 6jdLI IR) -1 - hyd-roatvef hyUnl methyl -1 -carfraoen-.2 -em- .3 -ca.rbpgcylaiLe Following a procedure similar to that described in Example 39, but using 50 mg of sodium 2-(2-oxo-4pyrrolidinylthio) -6=( (IR) -1-hydroxyethyI] -1-methyl1- carbapen-2-em-3-carboxylate and 55 mg of 5-methyl2- oxo-1,3-dioxolen-4-ylmethyl bromide, 50 mg of the title compound were obtained as a colourless powder.

Ultraviolet Absorption Spectrum (CH^CN) n®· 321.1 (ε - 8982).

Infrared Absorption Spectrum (CHCs3) cm : 1820, 1772, 1701, 1627.

Nuclear Magnetic Resonance Spectrum {CDCz^, 270 MHz) Sppm: 1.30 (3H, doublet, J » 7.33 Kz); 1.36 (3H, doublet, J - 6.22 Hz); 1.80 (IH, broad singlet); 2.21 (3H, singlet); 2.35 (IH, doublet of doublets, J - 17.58 & 6.04 Hz); 2.81 (1H, doublet of doublets, J - 17.58 & 8.80 Hz); 3.25 - 3.43 (3H, multiplet); 3.73 - 4.OS (2H, multiplet); 4.17 - 4.32 (2H, multiplet); 4.96, 5.OS (2H, AB, J « 13.93 Hz); .59 (1H, broad singlet).

EXAMPLES .47-.TQ_S.$ Ί0 E2C§S!Sl£_47 3.-(I^uiyryloay) ethvl. tlR, .55-,. 6S_) r_2^2r-QxQrlz, pyrrol idisylthio) -.6-. L (15)-1- b?hirQxy-e±M carbanen-2 -em-3-carboxylate Ultraviolet Absorption Spectrum (CH^CN) nm: 323. gxa&ple-18, i - (Cyclohexanecarbonyloxv) ethvl (IE, 5$,...8.8). Λ^_ί2^ρχο_-4pyrrolidinvlthio) -5-'l (IR).-1 -hvdro.xv®f hylJ^l^mephyl^l^ garbaa.en^.2 ultraviolet Absorption Spectrum (CH^O) λnm: 323.

Example. 45, • 30 1 - (pjya.loyloxy)ethyl. HR, 5$., 6SJ -2^12^<22gQr4^ pyrrol idinyl thio.) - 6- r.(iR).-i-hvdroxvefhvll £S£bgEfian2ji^ffirlr£S-Xb2S£la&a Ultraviolet Absorption Spectrum (CKgCN) 323. am: gxamalg,-.5..Q. iz&cgt2Qxyg£hyX—L1R,_5_S_._6S L- 2 -(2- oxo - 4 - pyrrol, idinvl -1 - methyl -1 - carbape.a^2-em5 lngarb_o3cy_l.ate Ultraviolet Absorption Spectrum (CH^CN) λ nm: max 323. g3£gmgle_51 CvcTohe3can.ecarbonylo3P/methvl_(lR^,__5S,-, . 6S) -2U2.~oxp-4pyrrolidiaylthio) -6 - f (IR) -l-hydroxyethvll -1-methyl.-lgarbageg-2 - em- 3 -jtarboxylh-t£ Ί5 Ultraviolet Absorption Spectrum (CH^CN) X^y nm: 323.

Example . 52 .C^clohexy.loxycarbcmylo3cyme.thyl- (IR, _ SS,-.6S) -2- (2-oxo-4gyrrolidinylthipl·-6-.(JIR).-Xhydroxyethyll -1 -methvlTL· garbapgn- 2 -,em- 3 "g^IQJgl&SS Ultraviolet Absorption Spectrum (CH^CN) Xmsjy nm: 323 .

Exgmp.le-5-3.

CyclQpea-tyloscycarbonylo: iethvl._(_1R, 5S,....6S)_-_ 2 - (2 - oxcL-Ar pyrgolidinylthio) - r fiR) -i-hyamsyschyll "VJ^£gltXr Ultraviolet Absorption Spectrum (CH^CN) X^^ nm: 323. .

Example 54 gad.lymi_ClR, 5g_3 gg) -2-.(l---methvl-2-oxo-4-pyrrolidinyl£Μ&Ιη$χ-Ιί1ΒΙ^Χ- hydroxyethyl 1 -1 - methyl -1 - carbapen. - 2 - em5 3 - carboxvlate_ Ultraviolet Absorption Spectrum (CH3CN) nm: 300.

Examgle_5£ Pivaloyloxymethyl (IR,. 5S, 6S)-2-(l-methyl~2-oxo-4pyrrolidinvlthio) -6 - Γ CLR) -l.-hydroxyethyll -i-methvlrlcarbaoen-2 -em-3 -carboxylate Ί5 Ultraviolet Absorption Spectrum (CH3CN) nm: 323.

Example 56 i"lIsoproPOxycarb.onyJpxv)_ethyl_Jjt.R, 5S, 6S) -2-_(iunethyl·? 2-oxo-4-pvrrolidinylthio),-6- r (IR) -1-hydroxy ethyllrJ. methyl,-1 - carbapen- 2 - em- 3 - carboxylate Ultraviolet Absorption Spectrum (CH3CN) nm: 323. > 30 .3 r&grcapfp - e ml of trifluoroacetic acid and 0.41 ml of trifluoromethanesulphonic acid were added, whilst ice-cooling, to a solution of 949 mg of 3-(4-methoxybenzylthio)pyrrolidin-2-one in 4 ml of anisole, and then the mixture was stirred at room temperature for 30 minutes. At the end of this time, the reaction mixture was concentrated by evaporation under reduced rpessure co leave a residue, which was purified by column chromatography through silica gel, eluted with a 10 : l by volume mixture of ethyl acetate and methanol, to give 728 mg of the title compound as an oil.

Nuclear Magnetic Resonance Spectrum (60 MHz, CDGs^) δ ppm: ' 1.75 ~ 3.05 (3H, multiplet); 3.30 - 4.04 (3H, multiplet); 8.12 (IH, broad singlet); 9.32 (IH, broad singlet).

PRBEmMTQMJm -(l) IS.6 g of triphenylphosphine were added to a 30 suspension of 3 g of 4-hydroxy"2-pyrrolidinone in 200 ml of tetrahydrofuran, and then the mixture was stirred at room temperature for S minutes, after which it was cooled to -20®C. A solution of 9.3 ml of diethyl azodicarboxylate in 9 ml .of tetrahydrofuran was added dropwise, whilst cooling at -12°C to -20°C, to the previous solution. The mixture was then stirred at 0 - 5°C for 5 minutes, after which it was again cooled to -20eC. 4..2 ml of thioacetic acid were then added dropwise to the mixture, whilst cooling at -18eC to -20°C. The mixture was then warmed to 0 = 5°C and stirred at that temperature for 2 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure. The residue was purified first by column chromatography through silica gel, eluted with a 10 : 1 by volume mixture of ethyl acetate and methanol, and then by column chromatography through silica gel, eluted with a 2 : 1 by volume mixture of acetonitrile and benzene, to give 2.45 g of 4-acetylthio-2~pyrrolidinone as colourless crystals.

Nuclear Magnetic Resonance Spectrum (CDCa^, 90 MHz) δ ppm: 2.00 - 4.44 (5H, multiplet); 2.31 (3H, singlet); 7.13 (1H, broad singlet). -(2) 1.82 of the product obtained in step (1) were dissolved in 30 ml of methanol. 2.3 ml of a 28% w/v methanol ic solution of sodium methoxide were added dropwise, whilst ice-cooling, to the previous solution, and then the mixture was stirred for 30 minutes. 12 ml of IN hydrochloric acid were then added, whilst ice-cooling, to the reaction mixture, which was then concentrated by evaporation under reduced pressure to leave a powdery residue. The residue was extracted with SO ml of ethyl acetate and the extract was dried over anydrous sodium sulphate. The extract was concentrated by evaporation under reduced pressure to give 1.35 g of the title compound as. colourless crystals.

Intrared Absorpcioo. Spectrum (KBr) ^may cm 1687, 1681, 1250.

Nuclear Magnetic Resonance Spectrum (CDCa^? 270 MH") δ ppm: 1.95 (IH, doublet, d - 7.0 Hz); 2.30 (IH, doublet of doublets, J «= 17.2 & 6.6 Hz); 2.80 (IH, doublet of doublets, J « 17.2 & 7.1 Hz); 3.31 (IH, doublet of doublets of doublets, J « 9.9, 5.2 & 0.8 Hz); 3.59 - 3.73 (IH, multiplet) ,3.80 (IH, doublet of doublets of doublets, J « 9.9, 7.3 & 0.7 Hz) ; 6.13 (IH, broad singlet).

Claims (22)

1. A compound of formula (I); in which: HO H R 1 \ / I C C-H / \ / \ H 3 C CH—CH C-S-(CHo) 2 -R a I I II C—N C / o COOR 5 R a a group of formula (III): R' \ / C R ? / \ / (CR' 2 )o C Γ l\ N-C R' J X R 2a 0 and in which: one of the symbols R' represents a bond of the compound of formula (X) f in said formula (III) the others of the symbols hydrogen atoms; R 1 represents a methyl group; (I) (III) to the remainder groups of R*' all represent R represents a hydrogen atom, a C^ - C g alkyl group or a C_ - C- alkanoyl group; and 1 Ό -COOR represents a carboxy group, a group of formula -COO , a group of formula -COOM^, where M is a 5 cation and 2c is the reciprocal of the valence of the cation M, or a protected carboxy group and, where -COOR represents a carboxy group, a group of formula -COOM^. or a protected carboxy group, the compound of formula (I) also contains an anion; fO χ is zero, or an integer from 1 to 3? p is zero or the integer 1 or 2? 15 and pharmaceutically acceptable salts and esters thereof. κ

2. A compound according to Claim 1, wherein R represents: a - C 2Q alkyl group; a - C ? cycloalkyl group; an aralkyl group in which the alkyl 20 part is C 1 - and the aromatic group is C_ - C. ,, and is unsubstituted or has at least one of 6 14 substituents (c), defined below; a C 2 - C g alkenyl group which is unsubstituted or has at least one of substituents (a) defined below; a halogenated 25 C x - C g alkyl group; a substituted silylalkyl group in which each alkyl part is - C g and the si lyl group has up to

3. Substituents selected from the group consisting of C^ - C g alkyl groups and phenyl groups which are unsubstituted or have at least one of 30 substituents (a) defined below; a phenyl group which is • unsubstituted or has at least one alkyl or acy lamino substituent? a phenacyl group which is unsubstituted or has at least one of- substituents (a) defined below? a cyclic or acyclic terpeayl group? an 35 alkoxymethyl group, in-which the alkoxy part is C„ - which is unsubstituted or is itself 1 o substituted by a single unsubstituted alkoxy group; an aliphatic acyloxymethyl group, in which the acyl group is an alkanoyl group,- a higher aliphatic acyloxyalkyl group in which the acyl group is an alkanoyl group, and the alkyl part is G? ~ C^; & cycloalkyl-substituted 5 aliphatic acyloxyalkyl group, in which the acyl group is an alkanoyl group, the cycloalkyl substituent is C 3 - C^, and the alkyl part is a C. ( - C g alkyl group; an alkoxycarbonyloxyalkyl group, in which the alkoxy part is C.,' - C J0 , and the alkyl part is 10 CL - C^; a cycloalkylcarbonyloxyalkyl or cycloalkyloxycarbonyl oxyalkyl group, in which the cycloalkyl group is Cg - C^ Q , Is mono- or polycyclic and is optionally substituted by at least one C l “ C 4 group, and the alkyl group is a 15 Ci - Cg alkyl group; a cycloalkylalkoxycarbonyloxyalkyl group in which the alkoxy group has a single eyeloalkyl substituent, the cycloalkvl substituent being Cg - C„ o and mono- or poly- cyclic; a terpenylcarbonyloxyalkyl or tarpenyloxycarbonyloxyalkyl group; a 20 5-alkyl- or 5-phenyl- substituted (2-oxo-l,3-dioxolen-4yl)alkyl group in which each alkyl group is C^ - Cg and in which the phenyl group is unsubstituted or has at least one of substituents (c); a phthalidyl group; an indanyl group,· or a 2-oxo-4,5,6,7-tetrahydro-1,325 bensodioxolen-4-yl group; jsubg t.i tuent s„ (ajUt hydroxy groups, cyano groups, carbamoyloxy groups, azido ' 30 groups, carboxy groups, nitro groups, oxo groups, halogen atoms, Ci - C g alkoxy groups, - C g ’ alkanoyl groups, C„ - Cg alkanoyloxy groups, C. - C, alkanoylamino groups, C„ - C„ xb ί / inn alkoxycarbonyl groups, groups of formula -NR R” 35 and -CONR 12 R 13 in which R 10 , R 11 , R 12 and R 13 are the same or different and each represents a hydrogen atom, a C. alkyl group or a C, - Cg alkanoyl group, 5 groups of formula -S0 2 NR 14 R 15 and ~S(O) k R 16 wherein R 14 , R 15 and R lc are the same or different and each represents a C^ - Cg alkyl group and k is zero or an integer 1 or 2, and groups of formula -NHS0 ? R 17 , -N«CR 18 NR 19 R 20 , -N=CR 21 CR 22 «NR 23 and -C(=NH)NR 24 R 25 17 25 wherein R to R are the same or different and 15 each represents a hydrogen atom or a C„ - Cg alkyl group; substituents (c): 20 C x - C 4 alkyl groups, alkoxy groups, - C 4 haloalkyl groups,, C... -C 3 alkylenedioxy groups, halogen atoms, cyano groups and nitro groups. . ς 25 3. A compound according to Claim 1, wherexn R represents: a C, - Cg alkyl group, a -C,_ cycloalkyl group; an aralkyl group in which the alkyl part is C^ - C 3 and the aromatic group is C- - C„ „ and is unsubstituted or has at least one of , ό 14 30 substituents (c), defined In Claim 2; a C 9 - Cg alkenyl group which Is unsubstituted or has at least one of substituents (a) defined in Claim 2; a halogenated - C^ alkyl group; a substituted silylalkyl group in which each alkyl part is C 1 - Cg and the silyl 35 group has up to 3 substituents selected from the group consisting of C_ - alkyl groups and phenyl groups which are unsubstituted or have at least one of substituents (a) defined in Claim 2; a phenyl group which is unsubstituted or has at least one C« - C 4 alkyl or acy lamino substituent; a phenacyl group which is unsubstituted or has at least one of substituents (a) 5 defined in Claim 2; a cyclic or acyclic terpenyl group; an alkoxymethyl group, in which the alkoxy part is CL - C,, , which is unsubstituted or is itself 14 substituted by a single unsubstituted alkoxy group; an aliphatic acyloxymethyl group, in which the acyl group Ί0 is a C 2 - C, alkanoyl group; a higher aliphatic acyloxyalkyl group in which the acyl group is a C_ - C, alkanoyl group,, and the alkyl oart is C 2 C 4' a ’ substituted aliphatic acyloxyalkyl group,, in which the acyl group is a 15 C^ - Cg alkanoyl group, the cycloalkyl substituent is C^ - C?, and the alkyl part is a C, - C^ alkyl group; a 1- (alkoxy carbonyl oxy) ethyl group,, in which the alkoxy part is C n - C„, and the alkyl part is C 1 - C^; a cycloalkylcarbonyloxyalkyl or 20 cycloalkyloxycarbonyloxyalkyl group, in which the cycloalkyl group is C 3 - C^,, is mono- or polycyclic and is optionally substituted by at least one C T - C A alkyl group,, and the alkyl group is a C 1 - C„ alkyl group; a cycloalkylalkoxycarbonyl25 oxyalkyl group in which the alkoxy group has a single cycloalkyl substituent, the cycloalkyl substituent being C 3 - C,_, and mono- or poly- cyclic; a terpenylcarbonyloxyalkyl or terpenyloxycarbonyloxyalkyl group; a 5-alkyl= or 5-phenyl- substituted ' 30 (2-oxo-l,3-dioxolen-4-yl)alkyl group in which each alkyl group is C^ - and in which the phenyl group is ’ unsubstituted or has at least one of substituents (c) ; a phthalidyl group; an indanyl group; or a 2-oxo-4„5„6,,7-tetrahydro-1,3-bensodioxolen-4“yl group.

4. A compound according to Claim 1, in which: 2 is 1; and 9g R ' represents a hydrogen atom, a alkyl group, or a C^ - C,, alkanoyl group.

5. A compound according to Claim 1, in which: the group of formula (III) represents a 2o. pyrrolidin-2-one-4~yl group, which has the group R W at its nitrogen atom; and 9s R represents a hydrogen atom, a methyl, ethyl, propyl, butyl, formyl, acetyl, propionyl or butyryl group.

6. A compound according to Claim 1, in which: the group of formula (III) represents a pyrroiidin-2~one-4~yl group, which has the group R 2a 20 at its nitrogen atom; and R 2a represents a hydrogen atom.

7. A compound according to any one of Claims 1 to 6, 2>5 wherein the l-hydroxyethyl group at the S-penem position is in the 1(R)-hydroxyethyl configuration.

8. A compound according to any one of Claims 1 to 7, wherein R 1 represents a hydrogen atom, and the penem 30 system has the (5B. SB) configuration.

9. A compound according to any one of Claims 1 to 7, wherein R represents a methyl group, and the penem system has the (IB. 5S, 68) configuration.

10. Pivaloyloxymethyl 2-(2-oxo-4-pyrrolidinylthio)-6-(1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3carboxyl&te and pharmaceutically acceptable salts thereof.

11. Pivaloyloxymethyl (IR, SS, SS)-2-(2-oxo 4-pyrrolidinvlthio)-6-((IR)-1-hydroxyethyl)-1-methyl-lcarhapen-2-em-3-carboxylate and pharmaceutically acceptable salts thereof.

12. (1-Methylcyclohexan-l-yl)carbonyloxymethyl 2-(2-oxo-4-pyrrolidinylthio)-6-(1-hydroxyethyl)-1-methyl1- carbapen-2-em~3-carboxylate and pharmaceutically acceptable salts thereof.

13. (l-Methylcyclohexan-l-yl)carbonyloxymethyl (IR, SS, 6S)-2-(2-oxo-4-pyrrolidinylthio)-6-((IR)-1hydroxyethyl]-1-methyl-1-carhapen-2- em-3-carboxylate and pharmaceutically acceptable salts thereof.

14. l-(Cyclopentyloxycarbonyloxy)ethyl 2- (2-oxo-4-pyrrolidinylthio)-6-(1-hydroxyethyl)-1-methyl1~carbapen-2-em-3-carboxylate and pharmaceutically acceptable salts thereof.

15. 1-(Cyclopentyloxycarbonyloxy)ethyl (IR, 55, 6S)-2-(2-oxo-4-pyrrolidinylthio)-6-((IR)-1hydroxyethyl)-1-methyl-1 -carbapen-2 - em-3 -carboxylate and pharmaceutically acceptable salts thereof.

16. A pharmaceutical composition comprising an .antibiotic in admixture with a pharmaceutically acceptable carrier or diluent, wherein the antibiotic is at least one compound of formula (I) ora 35 pharmaceutically acceptable salt or ester thereof, as claimed in any one of Claims l to 15. v

17. A composition according to Claim 16, formulated for oral administration.

18. A composition according to Claia 16, formulated for 5 parenteral administration.

19. - A process for preparing a compound according to any one of Claims 1 to 15, which comprises the steps: •JO (a) reacting a compound of formula (TV) : Ί5 HO H R 1 \ / I C C-H / \ / \ 97 H 3 C CH—CH C-R 2 1 | | || (IV) 0 COOR 20 20. (in which R is as defined in Claim 1, R 90 30 represents a group of formula -OR or -SO-R , xn which: 2° R represents: an alkanesulphonvl group, 25 represented by a methanesulphonyl, ethanesulphhonyl, propanesulphonyl, isopropanesulphonyl or butanesulphonyl group; an arylsulphonyl group, represented by a phenylsulphonyl, tolylsulphonyl, especially p-tolylsulphonyl, or naphthyl sulphonyl group,- a 30 dialkyIphosphoryl group, represented by a dimethylphosphoryl, diethylphosphoryl, dipropylphosphoryl, diisopropylphosphoryl, dibufylphosphoryl or dipentyIphosphoryl group; or a diarylphosphoryl group, represented by a 35 diphenylphosphoryl or ditolylphosphoryl group; represents an alkyl group. represented by a methyl, ethyl, propyl or isopropyl group; a haloalkyl group, represented by a fluoromethyl, chloromethyl, fluoroethyl, difluoromethyl, difluoroethyl, dichloroethyl, trifluoromethyl, or trifluoroethyl group; 5 a 2-acetyl- aminoethyl group; a 2-acetylaminovinyl group; an aryl group, represented by a phenyl or naphthyl group which may optionally be substituted with from 1 to 3 substituents, which may be the same or different and examples of the substituents include the 10 fluorine, chlorine and bromine atoms, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, nitro, hydroxy and cyano groups; a heteroaryl group represented by a pyridyl or pyrimidinyl 15 group which may optionally be substituted with from 1 to 3 substituents, which may be the same or different and examples of the substituent Include the fluorine, chlorine and bromine atoms and the methyl, ethyl, propyl and isopropyl groups; and ο o R represents a protecting group for a carboxylic acid); with a compound of formula (Vb): HS-(CEL) -R 11 - (Vb) z s [in which T VT ' 30 R represents said group of formula (III), in which, if required any active groups are protected, «. Is as ( defined in Claim 1, and X is a balancing anion] , to give a compound of formula (VI): HO H R 1 \ / I C C-H / \ / \ H 3 C CH—CH C-S-(CH 2 ) fj-R b , I I II (VI) 5 c-N-C / \ O COOR 28 T 28 [in which R , R and χ are as defined in Claim l, 10 and R^ 3 represents said group of formula (III) , in which, if required any active groups are protected, and which, if necessary contains a balancing anion], (b) and then, if necessary, removing protecting groups 15 and/or esterifying and/or salifying the resulting compound to give a compound of formula (X) or a pharmaceutically acceptable salt or ester thereof.

20. The use for the manufacture of a medicament for the 20 treatment or prevention of microbial infection of an antibiotic, wherein the antibiotic is at least one compound of formula (I) or a pharmaceutically acceptable salt or ester thereof according to any one of Claims 1 to 15.

21. , A process as claimed in Claim 19 substantially as described herei with reference to the Examples.

22. A compound whenever prepared by a process as claimed in any of 3 θ Claims 19 or 21.